Eighteen years ago, precisely in December 1998, the FDA approved a new class of pain reliever known as celecoxib, this drug is a selective cox-2 inhibitor, designed to retain the pain relieving properties of non steroidal anti- inflammatory drugs (NSAIDs) like ibuprofen and naproxen,but devoid of the gastrointestinal effects which afflicted the later. A month later,Pfizer and Pharmacia launched a brand of celecoxib known as celebrex, Merck also launched their brand with name vioxx amd both brand went into the market
Scientists believed that,beyond pain assuagement, that celebrex can reduce the formation of polyps within the colon of patients with familial adenomatous polyposis (FAP), a uncommon disease which when ignored can lead to colon cancer, this believe led the FDA to approve a supplemental use of celebrex in FAP patients, the companies (Pfizer and Merck), based on this hypthesis launched a long term study of celecoxib in cancer patients.
Then, on September 27, 2004, APPROVe (“Adenomatous Polyp Prevention on Vioxx”) which is the data safety monitoring board responsible for oversight of Merck’s study , came to an unpleasant conclusion. They recommended that the study be stopped because patients on the drug showed an elevated risk of strokes and heart attacks, especially in those who had been on Vioxx for over 18 months. Merck complied with recommendation and immediately withdrew Vioxx from the market. However, Celebrex was still on the market and other COX-2 inhibitors were in late-stage development, what would FDA do now? Was the increased cardiovascular (CV) risk unique to Vioxx, or did all COX-2 inhibitors suffer from adverse CV effects? To solve this problem, the FDA called a joint meeting of their Arthritis Advisory Committee and the Drug Safety & Risk Management Advisory Committee. This meeting lasted for about three days and consisted of 30 advisors–an unusually large number. It covered the spectrum of the properties of COX-2 inhibitors in order to understand the risk-benefit ratio that these drugs posed to patients. At the end of these three days, the joint committee voted to allow Celebrex to stay on the market as it became lucid that long-term use of other NSAIDs also posed Cardiovascular hazards. The FDA accepted this recommendation. In fact, one of the big outcomes of this meeting was that the non-selective NSAIDs also posed a Cardio vascular risk. Due to this, the FDA made the following change to the Celebrex label:
“Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.”
While this solved the problem in the interim, the FDA is now faced with another issue faced issue. Patients that suffer arthritis tend to be older, and cannot easily exercise due to joint pain–these are the very patients that are prone to heart disease. How should physicians best treat arthritis pain in this group? The FDA mandated Pfizer to sponsor a study to answer that question. Known as PRECISION (“Prospective Randomized Evaluation of Celebrex Integrated Safety vs. Ibuprofen or Naproxen”), the study was led by the esteemed cardiologist of the Cleveland Clinic, Dr. Steven Nissen and involved 24,081 patients, a third of whom were randomly assigned to Celebrex, a third each to prescription doses of ibuprofen and naproxen. The key criteria that qualifies for inclusion in the study were that patients had established Cardiovascular disease or increased risk for developing it. The primary outcome measured was death from Cardiovascular origin, including nonfatal myocardial, hemorrhagic death, non-fatal strokenand infarction.
The PRECISION results are out and were presented last month by Dr. Nissen at the just concluded American Heart Association meeting with simultaneous publication of the results in the New England journal of medicine. It is within safety to say that what the PRECISION investigators found would have stunned those attendees at the FDA Advisory Committee meetings held back in 2004. There were 188 deaths (2.3%) from CV causes for the Celebrex patients, 201 deaths (2.5%) for those on naproxen and 218 (2.7%) for the ibuprofen patients. In the New England Journal of medicine article, the authors state that “the PRECISION trial provides a strong evidence that statistically prove that cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with non-selective NSAIDs.” They go on to say that “the trial results do not support the widely held belief that treatment with naproxen, as compared to other NSAIDs, provides a better cardiovascular outcomes.”
However, the PRECISION results provided other revelations. While the primary aim of the trial was to assess Cardiovascular outcomes, other outcomes like gastrointestinal and renal were investigated as well. It is no surprise that the Celebrex had significantly fewer gastrointestinal safety issues–was that not why the drug was developed in the firt place? But the rates of renal adverse events and hospitalizations for high blood pressure were also significantly lower for Celebrex compared to ibuprofen (although on this effect, Celebrex and naproxen were no different.)
The study investigators aslo acknowledged the limitations of PRECISION :
Adherence and retention were lower than in most trials that assess cardiovascular outcomes, which reflects the challenges of long-term treatment of a painful condition in patients who frequently experience frustration with unrelieved symptoms and switch therapies or leave the trial. Low levels of adherence have also been found in previous pain studies.
The circumstance that surrounded the withdrawal of Vioxx from the market led to a barrel of attacks on the pharmaceutical industry. The industry, specifically Pfizer and Merck, were looked at as profiteers, committed not to patients but to profits