Burying the spectre of VIGOR with evidence from PRECISION
Though the VIGOR* trial ended many years ago, the outcomes its accompanying events continued to affect clinical practice, even when newer trials, such as PRECISION**, emerged to debunk much of the misconceptions generated by VIGOR.
Speaking from a live webcast, Professor Ernest Choy, head of Rheumatology and Translational Research at the Institute of Infection and Immunity, Cardiff University, UK, said the medical fraternity was only recently coming to terms with the PRECISION study’s findings, which was published towards the end of 2016.
PRECISION established that celecoxib’s cardiovascular risk is the same as conventional non-steroidal anti-inflammatory drugs (NSAIDs) including naproxen and ibuprofen. All-cause mortality, major gastrointestinal bleeds and adverse renal evens were also lower in celecoxib compared with naproxen. Similarly, celecoxib was found to cause less GI tract adverse events than ibuprofen or naproxen.
Additionally, observations from PRECISION-AMBP, which is a pre-specific substudy of the PRECISION trial, established that hypertension and increase in blood pressure was less frequent in celecoxib compared with naproxen and ibuprofen. Increases in creatinine, which was an investigator-reported adverse event, was also lower in the celecoxib group compared with those on ibuprofen.
In light of all the convincing evidence, earlier this year, Pfizer submitted a motion to the US FDA to consider changing the label of celecoxib and convened a special joint meeting in April, which was attended by the US Drug Safety and Risk Management advisory committee and the Arthritis Advisory committee. [Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605207.pdf]
At the end of the 2-day hearing, the committee voted in favour of celecoxib on the conclusion that it was posed no greater risk for heart attacks and strokes compared with naproxen and ibuprofen. Although, Choy said the reviewers cautioned that this recommendation “must be interpreted in the contact of the doses used in the (PRECISION) trial, which were prescription strength, and cannot be extrapolated to apply to intermittent or OTC dosing”.
VIGOR’s legacy of misconception
Choy said in the aftermath of VIGOR’s publication, the US FDA recommended that all COX-2 selective inhibitors carry a black box warning about the increased risk of heart attack and stroke. The European Medicines Agency (EMA) also issued guidelines warning physicians using COX-2 selective inhibitors on patients with ischaemic heart disease or stroke or risk of either disease.
“There were major public health concerns, which led to rofecoxib’s withdrawal from the market,” noted Choy. On top of this, the perception that naproxen was cardioprotective was also imprinted within the medical fraternity.
“As you know, for the last 2 decades, many rheumatologists and physicians were prescribing naproxen to patients (with osteoarthritic or rheumatoid arthritis) as they believed this drug was safer (in cardiovascular terms) and that led to a global increase of use of naproxen to treat musculoskeletal conditions,” said Choy.
It is hoped that the newer recommendations by the special panel meeting will finally put to rest all the confusion surrounding COX-2 selective inhibitors and other NSAIDs.
VIGOR*: Vioxx GI Outcomes Research PRECISION**: Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen PRECISION-AMBP***: Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen-Ambulatory Blood Pressure Monitoring