Major Celebrex Studies
CLASS Study: Celebrex Long-Term Arthritis Safety Study
One of the only long-term studies available on Celebrex, the CLASS study was designed to assess the long-term risks and benefits of NSAID use in patients with arthritis. The study compared the long-term effects of the NSAIDs Celebrex, Diclofenac, and Ibuprofen on 5,800 patients with Osteoarthritis and 2,200 patients with Rheumatoid Arthritis.
Although it was concluded that Celebrex did not carry a higher cardiovascular risk than the other study drugs, it was found that Celebrex combined with a low-dose aspirin regimen caused a four-fold increase in bleeding ulcers and other serious gastrointestinal complications 6 to 9 months into treatment.
Celecoxib Versus Naproxen and Diclofenac in Osteoarthritis Patients: SUCCESS-I Study
The SUCCESS-I study tested the effects of Celebrex compared to the non-selective NSAIDs in treating the pain of osteoarthritis. The study was notable because of its sample size, including over 13,000 participants from 39 countries, but it was not designed to measure cardiovascular risks. The goal of the study was to measure the comparative risk of gastrointestinal complications in patients using selective and non-selective NSAIDs. Patients were given either 200mg or 400mg of Celebrex, 100mg of Diclofenac, or 1000mg of Naproxen daily for 12 weeks.
It was concluded that Celebrex carried a lower risk of gastrointestinal complications, including bleeding ulcers, than non-selective NSAIDs, but did not provide better pain management. The study reported no significant difference in number of serious cardiovascular events during the study (10 in the Celebrex group compared to 1 in the NSAID group), however percentage notwithstanding it would seem that the Celebrex group had a ten-fold higher rate of cardiovascular complications.
APC Trial: Prevention of Sporadic Colorectal Adenomas with Celecoxib
The APC Trial tested the effects of daily Celebrex use in reducing colorectal polyp growth in patients who had undergone surgery to remove adenomas (non-cancerous growths in the colon and rectum). Over 2,000 patients participated in the placebo study beginning in 1999, receiving either 400mg or 800mg of Celebrex daily.
The 2004 withdrawal of Vioxx (Rofecoxib) from the market spurred great public debate over the safety of Celebrex and similar drugs, which resulted in the formation of the Cardiovascular Safety Committee (CSC) to oversee studies involving potentially risky drugs. Additionally, the APC trial was monitored by a Data Safety Monitoring Board (DSMB) which worked together with the CSC to examine the safety of the study. Study results were publicized reporting that Celebrex was associated with an increased risk of cardiovascular complications: specifically, the study found a 2.5% increased risk in patients receiving the lower dosage and a 3.4% increased risk in patients receiving the higher dosage compared to placebo. As a result, the CSC and DSMB made the decision to suspend the use of the drug in the study.
In 2008, the five-year results of the trial became available, measuring the effects of three years of Celebrex therapy after a two-year cessation of the drug. The results showed a 41% decrease in adenomas in patients who received 400mg of Celebrex daily, and a 24% decrease in patients who received 800mg daily during the course of the study. It was still concluded that the drug carried an increased risk of cardiovascular events, particularly in patients with at least two preexisting conditions putting them at greater risk of heart attack or stroke. For these patients, the risk of heart attack and stroke was 3-6% higher than in the placebo group. In patients with no preexisting risk factors, there was still a 1-3% increased incidence of cardiovascular events over placebo.
ADAPT Trial: Alzheimer’s Disease Anti-Inflammatory Prevention Trial
Beginning in 2001, the ADAPT trial, sponsored by the National Institute of Aging, tested the effectiveness of Celebrex and Naproxen (compared to placebo) at delaying the onset of Alzheimer’s Disease in just over 2600 patients with a family history of the disease. The theory was that treating the inflammation in the brain associated with Alzheimer’s might stave off the symptoms of the disease. Study participants received either 400mg of Celebrex daily or 440mg of Naproxen daily. The study was monitored by the Treatment Effects Monitoring Committee (TEMC). Two scales were used to measure the cognitive changes of the patients in the study: the Alzheimer’s Disease Assessment-Cognitive Behavior (ADAS-Cog) and the Clinician’s Interview-Based Impression of Change Plus (CIBIC-Plus).
During the study, the ban of Vioxx and interruption of the concurrent APC trial caused the ADAPT study to receive additional scrutiny. The results at that time showed a slightly higher rate of cardiovascular events in patients taking Naproxen than those taking Celebrex. Because Celebrex was determined unsafe at that time for use in the APC trial and the partial results of the ADAPT trial showed an even higher risk associated with Naproxen, the ADAPT trial, intended to run for 5-7 years, was cut short after 23 months.
A Brief History of Celebrex
1998: Celebrex is approved for the treatment of osteoarthritis and rheumatoid arthritis
When Celebrex was approved by the FDA in 1998, it was a promising new treatment for the millions of people living with the pain of osteoarthritis (approximately 27 million in the US alone) and rheumatoid arthritis (1.7 million in the US). The use of the selective COX-2 inhibitor was intended to prevent the adverse effects that were believed to be linked to the inhibiting of the COX-1 enzyme.
Celebrex was tested against other NSAIDs and against placebos in 2100 patients with rheumatoid arthritis (RA) and 4200 patients with osteoarthritis (OA). It was found to be equally as effective as other NSAIDs at relieving pain and inflammation compared to placebo. With its approval of the drug, the FDA mentioned the possibility that Celebrex carried the risk of cardiovascular complications.
At the same time that Pfizer was preparing to release Celebrex, Merck & Co. was preparing to release their similar drug, Vioxx, which would be marketed to the same population of patients. Celebrex beat Vioxx to the shelves narrowly, enjoying a year of virtually unrivaled sales until the release of Vioxx in 1999. Both Pfizer and Merck & Co. went to great expense to market their respective new drugs to arthritis sufferers, including an emphasis on direct-to-consumer print and television advertising.
Original Package Warnings for Celebrex
With its initial release, Celebrex came with a package warning about the danger of ulcers and possible interference with platelet function, as has been associated with the entire class of NSAID drugs. Because the original clinical trials were only 6 to 12 months in duration, it was undetermined whether Celebrex posed a risk of serious cardiovascular events with prolonged use.
1999: Packaging Change for Celebrex Warns of Interaction with Warfarin
In 1999, Pfizer changed the package warning on Celebrex to include the danger of interaction with the drug Warfarin, which is an anticoagulant agent. During the original clinical trials, there was no evidence of a particularly adverse reaction with Warfarin, but soon after the release of the drug, the FDA received several reports of patients who had experienced fatal cardiovascular events while taking Warfarin and Celebrex. In several reported cases of patients taking Warfarin, Celebrex reacted with the drug to enhance its anticoagulant effects to unsafe levels. This not only contributed to the possibility of cardiovascular events, but increased the risk of bleeding to death, especially if stomach or intestinal perforations are present.
1999: FDA Approves Celebrex for the Treatment of Familial Adenomatous Polyposis
In 1999, Celebrex was approved by the FDA for the treatment of Familial Adenomatous Polyposis (FAP), a rare but serious hereditary condition in which the patient develops colon polyps that tend to develop prematurely into colon and rectal cancer. During a six-month trial of 83 patients with FAP, there was a 28% reduction in colon polyps in patients who took 400mg of Celebrex daily, compared to a 5% reduction with placebo.
It was emphasized that the use of Celebrex in treating FAP should not be considered a substitute for more traditional treatments, which typically include surgical reduction of tumors and frequent endoscopic surveillance. Coupled with these aggressive techniques for managing FAP, Celebrex was believed to reduce the growth of polyps and thereby aid in the prevention of cancer development in these patients.
2004: Vioxx is Withdrawn from the Market
After studies showed that COX-2 Inhibitor Vioxx (Rofecoxib) caused a dramatic increase in fatal cardiovascular events, including heart attack and stroke, Merck & Co. withdrew the drug in September of 2004. These risks were directly proportional to the length of treatment and dosage that patients received. The Vioxx ban caused a hike in sales for competing drugs Celebrex and Bextra, the only two remaining COX-2 Inhibitors on the market.
In response to the ban of Vioxx, Pfizer agreed publicly that there was also reason for concern surrounding Celebrex, and possibly the entire class of COX-2 Inhibitors, and the risk of death by gastrointestinal perforation, heart attack, or stroke. Pfizer agreed that further studies, as well as meta-research on existing studies, were necessary to determine the absolute safety of the drug. As a concession, Pfizer agreed to suspend direct-to-consumer advertising until further notice from the FDA.
The FDA announced that there was “great concern” over Celebrex and its class of drugs (NSAIDs and COX-2 Inhibitors in particular), but at that time the FDA decided to “keep its options open” regarding the approval of Celebrex. At the same time, doctors and consumers alike were reminded to seek alternative treatments whenever possible.
2005: Bextra is Withdrawn from the Market
In 2005, Bextra (valdecoxib) was withdrawn from the market on recommendation of the FDA after, as in the case of Vioxx, it was discovered that the drug caused an increased risk of serious cardiovascular events, particularly in patients recovering from bypass or other heart surgery. Bextra, manufactured by G.D. Searle & Co. and sold by Pfizer, was also found in rare cases to cause a fatal skin reaction which, despite a related black box warning, was part of the reason for the drug’s withdrawal.
The Bextra ban, though a blow to the pharmaceutical company, was a blessing for the sales of Celebrex, which enjoyed an all-time high after the Bextra ban. At that time, Celebrex became the only COX-2 Inhibitor on the market, and for many chronic pain sufferers, steroidal pain killers are not desirable as an alternative to NSAIDs because of their side effects. Thus, the FDA determined that the benefits of Celebrex outweighed the risks, and the drug was allowed to stay on the market, but with additional safety information enclosed. It was also suggested to the medical community that all patients be advised of the risks and alternatives to NSAIDs, and that they be prescribed in the lowest effective doses. Additionally, it was reiterated that Celebrex is not recommended for patients at otherwise higher risk of cardiovascular complications, patients who are pregnant or breast feeding, or patients with liver problems.
2005: FDA Approves Celebrex for the Treatment of Ankylosing Spondylitis
In 2005, the FDA added Ankylosing Spondylitis to its list of approved uses for Celebrex. Ankylosing Spondylitis, also called spinal arthritis, is a chronic inflammatory disease which can cause rigidity and loss of movement in the neck and spine. During the two pre-approval clinical trials of 6-12 weeks in duration, patients took between 100mg and 400mg of Celebrex daily. The study measured patients’ pain intensity and range of motion, and around half of subjects showed significant improvement compared to placebo. Patients taking the highest dose (400mg daily) showed the most improvement on average. Long-term results of the study are not available.
2006: FDA Approves Celebrex for the Treatment of Juvenile Rheumatoid Arthritis
In 2006, The FDA approved the use of Celebrex for the Treatment of Juvenile Rheumatoid Arthritis (JRA). This disease affects an estimated 300,000 patients aged 2-17 in the US alone. After a six-month clinical study showing only mild to moderate side effects and no other complications, the drug received approval. Celebrex has never been tested on patients under 2 years of age. The study results did not rule out cardiovascular complications with continued and prolonged use, as was seen in the case of Vioxx, but based on the patients’ reports of pain relief the benefits were seen to outweigh the risks.
There is debate about whether longer-term testing should be necessary before a drug can be deemed safe for new usages, especially since drug companies are anxious to release new drugs in order to make sales. It is still unknown whether the treatment of JRA with Celebrex may carry a greater risk of serious complications with prolonged use. Official reports on the long-term effects of Celebrex on JRA sufferers are not yet available, but the drug is still currently being prescribed to JRA sufferers.
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