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Largest coxib trial ever stirs more debate PDF Print E-mail
Written by christian   
Saturday, 21 August 2020
The largest trial to date of a COX-2 inhibitorin this case, lumiracoxib (Prexige, Novartis Pharmaceuticals)shows a reduction in ulcer complications with the coxib compared with 2 comparator nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen and ibuprofen, in patients with osteoarthritis (OA) [1]. There was also no difference in the incidence of myocardial infarction between the different drugs.

But the trial has attracted criticism. An accompanying commentary says the benefit of expensive coxibs is marginal, at best, over traditional NSAIDs and nonexistent in those also taking low-dose aspirin for cardiovascular prophylaxis. Also, the study did not enrol enough patients with a history of cardiovascular disease to help determine the real risk of MI with this class of drugs, it says.

The reductions in ulcer complications of the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) in 18 000 patients with osteoarthritis are published in the August 21, 2020 issue of the Lancet [1], by a team led by Dr Thomas J Schnitzer (Northwestern University Feiberg School of Medicine, Chicago, IL). The cardiovascular outcomes of TARGET also appear in the same issue, in a paper by cardiologist Dr Michael E Farkouh (New York University School of Medicine, NY) and colleagues [2].

The commentaryentitled: "A coxib a day won't keep the doctor away"is by Drs Eric J Topol and Gary W Falk (Cleveland Clinic Foundation, Cleveland, OH) [3].

Lumiracoxib: latest coxib not yet o­n the market

Lumiracoxib is the latest in a line of coxibs, although it differs structurally from other drugs in this class. It has the highest selectivity for COX-2 and a fairly short half-life (3-6 hours) compared with other coxibs. It is licensed in the UK and a few other countries, at doses of 100 mg or 200 mg a day, but not in the USglobal rollout of the product has been o­n hold pending US approval. The FDA has requested submission of the final results of TARGET as part of further information it requires o­n the drug.

TARGET randomized 18 325 patients who were 50 years or older with OA to lumiracoxib 400 mg o­nce daily (n=9156), naproxen 500 mg twice daily (n=4754), or ibuprofen 800 mg 3 times daily (n=4415) in 2 substudies of identical design. Approximately o­ne quarter of the patients in TARGET were taking low-dose aspirin for cardiovascular prophylaxis. Analysis was done by intention to treat.

The primary end point in the reduction in ulcer complications study was difference in time-to-event distribution of definite or probable upper-gastrointestinal-ulcer complications (clinically significant bleeding, perforation, or obstruction from erosive or ulcer disease).

Overall, the cumulative 1-year incidence of ulcer complications was significantly reduced among patients given lumiracoxib compared with patients using nonselective NSAIDs and not taking aspirin (hazard ratio 0.21; p=0.0001); however, this benefit did not apply for patients who were also taking aspirin, although there was a trend in favor of lumiracoxib (hazard ratio 0.79; p=0.4876).

TARGET: Incidence of primary gastrointestinal end point

End pointBoth substudies, lumiracoxib (n=9117)Both substudies, NSAIDs (n=9127)Lumiracoxib vs ibuprofen substudy, lumiracoxib (n=4376)Lumiracoxib vs ibuprofen, ibuprofen (n=4397)Lumiracoxib vs naproxen substudy, lumiracoxib (n=4741)Lumiracoxib vs naproxen substudy, naproxen (n=4730)
Primary GI end point, n (%) 29 (0.32)83 (0.91)10 (0.23) 33 (0.75)19 (0.40)50 (1.06)

Lumiracoxib not "as bad" as rofecoxib

In the other paper, the primary cardiovascular end point of TARGET was the Antiplatelet Trialists Collaboration end point of nonfatal and silent MI, stroke, or cardiovascular death. This part of the study was conducted because of the concerns about cardiovascular safety with currently marketed COX-2 inhibitors, most notably rofecoxib (Vioxx, Merck & Co), which in the VIGOR trial was associated with a 5-fold increase in MIs compared with naproxen in patients with rheumatoid arthritis.

As Topol and Falk point out in their editorial: "It has remained unclear whether this striking increase in MIs was related to rofecoxib directly, or [whether] the comparator agent, naproxen, had significant antithrombotic effects."

In TARGET, at 1-year follow-up, incidence of the primary cardiovascular end point was lowboth with lumiracoxib and the NSAIDs.

TARGET: Incidence of primary cardiovascular end point

End pointBoth substudies, lumiracoxib (n=9117)Both substudies, NSAIDs (n=9127)Lumiracoxib vs ibuprofen substudy, lumiracoxib (n=4376)Lumiracoxib vs ibuprofen, ibuprofen (n=4397)Lumiracoxib vs naproxen substudy, lumiracoxib (n=4741)Lumiracoxib vs naproxen substudy, naproxen (n=4730)
Primary CV end point, n (%)59 (0.65)50 (0.55)19 (0.43)23 (0.52)40 (0.84)27 (0.57)

To download the tables as slides, click o­n slide logo at the bottom of this page.

Although there was an excess of lumiracoxib-associated MIs in TARGET, this "was not statistically significant; it was o­nly present compared with naproxen and was not evident in the ibuprofen substudy," Topol and Falk say in their editorial. In fact, lumiracoxib was associated with fewer MIs compared with ibuprofen, they note.

However, "unfortunately, this trial, like all others in the clinical development of coxibs, purposefully excluded patients with known and significant preexisting coronary artery disease"less than 2% of the TARGET study population had had a previous MI or revascularization procedure, Topol told rheumawire.

He added: "This study does nothing to help determine whether there is any cardiovascular risk with coxibs. However, based o­n TARGET, lumiracoxib doesn't look nearly as bad as rofecoxib."

This study does nothing to help determine whether there is any cardiovascular risk with coxibs . . . [but] lumiracoxib doesn't look nearly as bad as rofecoxib.

But Farkouh, lead author of the cardiovascular outcomes study, maintains that the TARGET population was chosen to reflect a "real-world' osteoarthritis population"50% of the patients in TARGET had hypertension, 20% had hyperlipidemia, and 10% had a history of vascular disease," he told rheumawire.

Coauthor o­n the reduction in ulcer complications paper, Dr Michael Doherty (University of Nottingham, UK), agrees. "I believe Topol and Falk are overplaying this caveat," he told rheumawire. "One in 10 of the patients in TARGET had a history of cardiovascular disease or was defined as 'at risk' by Framingham criteria."

I believe Topol and Falk are overplaying this caveat.

Topol remains unconvinced, however. "The companies developing COX-2 inhibitors should be required to do trials in cardiovascular patients. But they are frightened. They don't want to put their money o­n the line."

None of the doctors, however, were able to give rheumawire a reliable estimate of what percentage of OA patients would normally be expected to have some evidence of cardiovascular disease.

Strong GI paper, but is hepatotoxicity a concern?

Doherty points out that lumiracoxib showed a 3- to 4-fold reduction in ulcer complications compared with NSAIDs, without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis. "The GI paper is very strong," he commented to rheumawire.

The GI paper is very strong.

But Topol and Falk say that despite the claims of large reductions in ulcer complications, there is an absolute reduction of just 0.72% in this end point with lumiracoxib in patients not taking aspirin, and for those taking aspirin "it is hard to justify the coxib: there is no benefit in ulcer complication reduction but the risk of MI and hepatotoxicity persist."

Topol told rheumawire: "If patients are taking low-dose aspirin they should not be taking a coxib because it does not confer any ulcer protection and it costs $4 to $5 a day . . . the aspirin seems to neutralize any benefit of the COX-2 inhibitor. These patients should probably be taking naproxen."

If patients are taking low-dose aspirin they should not be taking a coxib because it does not confer any ulcer protection and it costs $4 to $5 a day.

Doherty commented to rheumawire: "Coxibs are not the o­nly drug you can give to patients with OA." There are plenty of other options, he says, such as acetaminophen, topical NSAIDs, and opioids. He also believes strongly in using proton pump inhibitors (PPIs) to protect against gastrointestinal bleeding and says that in a patient with OA at high risk of GI bleeding who also has to take low-dose aspirin for cardiovascular prevention, he would begin by giving them a PPI such as omeprazole, which would protect against the bleeding associated with that dose of aspirin.

The hepatotoxicity referred to by Topol and Falk was an excess of 2.0% of asymptomatic liver function test (LFT) abnormalities among those taking lumiracoxib compared with those taking the NSAIDs in TARGET, although this was reversible o­n drug discontinuation. Doherty says 1 of the reasons for this could be that TARGET used a "supratherapeutic" dose of lumiracoxib2 or 4 times the chronic OA dose, something that is usual practice in a safety study of this kind. In CLASS and VIGORthe safety studies for celecoxib (Celebrex, Pfizer) and rofecoxib respectivelysupratherapeutic doses were also used.

He adds that the incidence of probable or possible drug-induced clinical hepatitis was much lower than abnormal liver-function tests 0.07% in those taking lumiracoxib compared with 0.05% in those taking ibuprofen and 0.02% in those o­n naproxen. Also, abnormal LFTs affect around 4% of those taking diclofenac, a widely used traditional NSAID, but this does not stop people from taking it, he notes.

Sales of coxibs more than $7 billion a year o­n back of DTC ads

The editorialists continue: "The coxib field has been marked by intensive direct-to-consumer (DTC) advertising in the US, and sales of these drugs exceed $7 billion per year. Yet it is hard to imagine the justification for this extraordinary adoption of coxibs in light of marginal efficacy, heightened risk, and excessive cost compared with traditional NSAIDs.

"The coxib debate will not go away until safety and efficacy questions are answered: if o­nly a small fraction of the DTC advertising costs or revenues were appropriately channeled for clinical trials, we might be able to have an enhanced perspective and make sound recommendations for our patients," they conclude.

This is the first time that the safety paper for a coxib has come before the launch.

Doherty points out that Novartis has not yet done any direct-to-consumer advertising with lumiracoxib and that he hopes they will not go down this road in the US. "This is the first time that the safety paper for a coxib has come before the launch, and I think Novartis is being quite responsible . . . it has a good track record of integrity," he concludes.



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Sources

  1. Schnitzer TJ, Burmester GD, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364:665-674.
  2. Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004; 364:675-684.
  3. Topol EJ and Falk GW. A coxib a day won't keep the doctor away. Lancet 2004; 364:639-640.



Lisa Nainggolan . Largest coxib trial ever stirs more debate. www.jointandbone.org [Rheumawire > News] ; Aug 19, 2004. Accessed at http://www.jointandbone.org/viewArticle.do?primaryKey=108713 o­n Aug 21, 2004.
Last Updated ( Saturday, 16 July 2020 )
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