COX-2 selective inhibitor is a form of NSAID that directly targets COX-2, an enzyme responsible for inflammation and pain. This type of medicine is often used to treat arthritis.
In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their synthesis, cyclooxygenase. Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-I, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-II, are responsible for inflammation and pain. The existing nonsteroidal antiinflammatory drugs (NSAIDs) differ in their relative specificities for COX-II and COX-I; while aspirin is equipotent at inhibiting COX-II and COX-I enzymes in vitro and ibuprofen demonstrates a sevenfold greater inhibition of COX-I, other NSAIDs appear to have partial COX-II specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications. A search for COX-II-specific inhibitors resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib, marketed under the brand names Bextra, Celebrex, and Vioxx respectively. Bextra and Vioxx are about 300 times more potent at inhibiting COX-II, than COX-I, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such side effects previously or had comorbidities that could lead to such complications. Celebrex is approximately 30 times more potent at inhbiting COX-2 than COX-1. On September 27, 2004 Vioxx (Rofecoxib) was withdrawn voluntarily from the market, due to an increased risk of myocardial infarction and stroke. At present it is unclear whether this side effect pertains also to other drugs of this group or is specific for Vioxx.
Although individual reactions to particular NSAIDs vary, in general the efficacy of COX-II inhibitors has proved similar to that of other NSAIDs, as expected since both classes of drug inhibit the desired target, the action of COX-II prostaglandins. The drugs's effectiveness is similar to that of traditional NSAIDs such as ibuprofen, diclofenac, or naproxen.
Early COX-2 inhibiting drugs
Celebrex and Vioxx were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States. By October 2000, their US sales exceeded 100 million prescriptions per year for $3 billion, and were still rising, sales of Celebrex alone reaching $3.1 billion in 2001. A Spanish study found that between January 2000 and June 2001, 7% of NSAID prescriptions and 29% of NSAID expenditures were for COX-II inhibitors. Over the period of the study, COX-II inhibitors rose from 10.03% of total NSAIDs prescribed by specialty physicians to 29.79%, and from 1.52% to 10.78% of NSAIDs prescribed by primary care physicians (98.23% of NSAIDs and 94.61% of COX-II inhibitors were prescribed by primary care physicians). For specialty physicians, rofecoxib and celecoxib were third and fifth most frequently prescribed NSAIDs but first and second in cost, respectively; for primary care physicians they were ninth and twelfth most frequently prescribed NSAIDs and first and fourth in cost.
The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials in JAMA, the Celecoxib Long-term Arthritis Safety Study (CLASS) study, and the Vioxx Gastrointestinal Outcomes Research (VIGOR) study. Both publications concluded that COX-II specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus naproxen for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations, obstructions and bleeding) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health.
In a metaanalysis of eight osteoarthritis studies, the incidence of withdrawal because of adverse gastrointestinal events was 3.5% for Vioxx, compared to 4.8% for ibuprofen, diclofenac, or nabumetone (Relafen). Endoscopic studies of patients receiving Celebrex 50-400 mg twice daily for 12-24 weeks found rates of upper gastrointestinal complications similar to placebo and significantly lower than naproxen 500 mg twice daily and ibuprofen 800 mg three times daily, but not statistically significantly different from patients receiving diclofenac 75 mg twice daily.11 The analysis found that Vioxx provided significant gastrointestinal benefits in patients both at high risk and at low risk of developing gastrointestinal problems; patients at low risk still had 88% fewer gastrointestinal problems with Vioxx.
The results of the CLASS study were confirmed by the Successive Celecoxib Efficacy and Safety Studies (SUCCESS) study, which examined the effectiveness and safety of celecoxib 200 mg and 400 mg daily and how well it was tolerated by patients in terms of side effects, compared with the most common NSAID regimens in the countries studied (diclofenac 100 mg daily and naproxen 1000 mg daily). SUCCESS showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain of arthritis, and caused fewer gastrointestinal ulcers or ulcer complications (such as perforations or bleeding) and fewer upper gastrointestinal side effects, e.g. 29% less chance of having nausea and 22% less chance of abdominal pain. In addition, hospitalization rates for upper gastrointestinal problems were 2 to 4 times lower with celecoxib, and because there were fewer side effects, there was 23% less chance of a celecoxib patient stopping treatment. The study also found that there was no real advantage to taking a bigger dose of celecoxib: the 200 mg dose was found to be just as effective as the 400 mg dose.
The VIGOR study was followed by the Assessment of Difference between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) study, which showed that 9.1% of people taking Vioxx received a gastro-protective medicine compared with 11.2% of people taking naproxen, a reduction of 19%. In addition, after 3 months, 5.9% of people stopped taking Vioxx compared with 8.1% who stopped taking naproxen, a reduction of 27%. ADVANTAGE was the first study comparing the gastrointestinal tolerability of Vioxx and naproxen in a group that included patients taking low-dose aspirin for cardiovascular reasons. This was followed by the Experience with Vioxx in Arthritis (EVA) survey of 5,986 Belgian physicians and 74,192 people with osteoarthritis, which found that, after 12.5 or 25 mg of Vioxx once daily for 30 days, 80% of the patients wished to continue treatment with Vioxx and more than 80% of doctors said they would continue prescribing Vioxx. The preference to continue taking Vioxx was especially strong in people who previously treated with older NSAIDs.
In a six week long study comparing Vioxx 25 mg once daily, Vioxx 12.5 mg once daily, Celebrex 200 mg once daily, and acetaminophen 1,000 mg four times daily for osteoarthritis of the knee, higher dose Vioxx was found to be superior to the other three treatments for reduction of nocturnal pain, and superior to Celebrex and acetaminophen for reduction of resting pain. At six weeks, 60% of high dose Vioxx patients reported a good or excellent response, compared to 46% of Celebrex patients and 39% of acetaminophen patients. Low dose Vioxx was not found to be statistically significant from Celebrex at this dose. Similar results were found for early response to therapy.
However, when the FDA later presented more complete data from the CLASS and VIGOR trials on its web site, the results were less certain. The CLASS trial was revealed to also have twelve and fifteen month time points which had not been discussed in the JAMA publication; in this segment of the trial, the number of ulcer-related complications for Celebrex caught up to the control NSAID group. Similarly, the complete VIGOR study data revealed that in fact, when all adverse events, not just gastrointestinal, were tabulated, the patients receiving VIOXX had suffered (barely) significantly higher incidence of adverse events overall than the control NSAID group. In particular, the risk of serious cardiovascular thrombotic events, e.g. myocardial infarction, was 1.7% in the VIOXX patients versus 0.7% in the control group, and there were significantly more withdrawals in the Vioxx group for causes including hypertension, edema, hepatotoxicity, heart failure, or pathological laboratory findings. The mean increases in systolic and diastolic blood pressure in the Vioxx group were 4.6 mmHg and 1.7 mmHg respectively, compared to 1.0 and 0.1 mmHg in the control NSAID group. An estimated 43,000,000 Americans, nearly one out of six, suffers from arthritis. However, 42% (18 million) of these also suffer from hypertension. Therefore, the promise of better patient outcomes and lowered medical costs from use of COX-II inhibitors may not be as great as previously hoped. Questions remain regarding the relative safety and cost effectiveness of this new class. While endoscopic evidence of gastrointestinal damage is frequently seen in studies of nonspecific NSAIDs, the actual incidence of clinically evident symptoms and patient discomfort is much lower; furthermore, in cases of short-term therapy, any such damage generally reverses itself quickly after termination of the drug.
Combinations of drugs
A model comparing the theoretical relative frequency of gastrointestinal side effects and cost effectiveness of celecoxib, nonspecific NSAIDs alone, NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAIDs plus misoprostol, and diclofenac/misoprostol, found the lowest probability of adverse gastrointestinal events for celecoxib, followed by NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAID plus misoprostol, diclofenac/misoprostol, and NSAID alone. In total cost, including drug plus treatment of any gastrointestinal effects, the lowest cost treatment was celecoxib, followed by NSAIDs alone and diclofenac/misoprostol, with the other NSAID plus gastrointestinal protection regimens being much more costly. Similarly, a model of cost effectiveness of rofecoxib and celecoxib compared to high-dose acetaminophen or ibuprofen, with and without misoprostol, in patients with osteoarthritis of the knee found that acetaminophen had the lowest cost for average patients. For those not responding to acetaminophen, ibuprofen was the most cost effective treatment by a large margin, but for those who did not respond to acetaminophen and had a high risk of gastrointestinal damage, rofecoxib was the most cost effective treatment.
Risks and side effects
This cardiovascular risk of COX-II specific inhibitors is not surprising since prostaglandins are involved in regulation of blood pressure by the kidneys. Therefore, cardiovascular effects of NSAIDs prescribed for arthritis pain and inflammation need to be considered when choosing the appropriate medication for each patient. A French study of osteoarthritis patients over 65 years of age determined that, compared to Celebrex (200 mg once daily), patients taking Vioxx (25 mg once daily) suffered a two-fold increase in clinically significant edema and 60% more frequent increases in systolic blood pressure greater than 20 mmHg, as early as the second week of treatment. This has significant implications, since it has been estimated that every 2 mmHg increase in blood pressure raises the risk of stroke by two thirds and the risk of myocardial infarction by one third, suggesting that Celebrex may be a better choice for hypertensive patients or those at risk for edema. In addition, COX-II inhibitors lack some of the platelet inhibiting properties of aspirin and other nonspecific NSAIDs and may, directly or indirectly, lead to increased risk of thrombosis, particularly in high risk patients where low dose aspirin therapy is warranted. On the other hand, this property makes them a better choice for perisurgical pain management, where inhibition of blood clotting would be problematic.
There are other differences between Celebrex and Vioxx that influence prescribing practices. Patients with known sensitivity to sulfa drugs are likely to be sensitive to Celebrex as well, due to similarity in structure. Vioxx has a more rapid onset and is approved for acute pain as well as osteoarthritis, while Celebrex is approved for rheumatoid arthritis as well as osteoarthritis.3
Considerations for prescription
A key assumption made in early COX II cost-effectiveness studies was lower cost due to a reduction in coprescription of agents used to protect the gastrointestinal tract from traditional NSAIDs. However, if gastroprotective agents continue to be coprescribed along with COX-II inhibitors, there would seem to be no advantage to the use of these higher cost NSAIDs. Similarly, in patients who take aspirin for cardiovascular benefit, with its attendant gastrointestinal irritation, prescription of COX-II inhibitors to avoid gastrointestinal irritation would seem to offer no advantage. This was confirmed by the CLASS study, which found significantly lower incidence of upper gastrointestinal complications alone and combined with symptomatic ulcers in patients taking Celebrex 400 mg twice daily, compared to ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily; but this freedom from gastrointestinal complications was lost in patients taking concurrent low dose aspirin.
- "Understanding NSAIDs: from aspirin to COX-2"; Gary A. Green; Clin Cornerstone 3(5):50-59, 2001.
- "COX-2 inhibitors: A CLASS act of just VIGORously promoted"; Samir Malhotra, N. Shafiz, P. Pandhi; Medscape General Medicine 6(1), 2004.
- "At what care level are cyclo-oxygenase-2 inhibitors prescribed?"; Montero, Fernandez MJ, Rodriguez, Alcala FJ, Valles Fernandez N, Lopez de Castro, F, Esteban, Tudela M, Cordero, Garcia B; Aten Primaria 2002 Oct 30:363-7.
- "You and A: Arthritis drugs. Pain and confusion"; Francesca Lunzer Kritz; Washington Post; Sept. 4, 2001; HE01.
- "Vioxx (rofecoxib) reduces night-time osteoarthritis pain better than celecoxib or acetaminophen"; European League Against Rheumatism (EULAR) conference proceedings.
- "Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.
- "Economic evaluation of celecoxib, a new cyclo-oxygenase-2 specific inhibitor, in Switzerland"; JV Chancellor, E. Hunsche, E. de Cruz, F. P. Sarasin; Pharmacoeconomics 2001; 19 Suppl 1:59-75.
- "The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis"; C. C. Kamath, H. M. Kremers, D. J. Vanness, W. M. O'Fallon, R. L Cabanela, S. E. Gabriel; Value Health 2003, Mar-Apr;6 (2); 144-57.
- "Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
- "Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.