Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7352.1488 (Published 22 June 2002) Cite this as: BMJ 2002;324:1488All rapid responses
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Editor,
Schumacher et al report etoricoxib to be equivalent to
indometacin as an analgesic for acute gout. This is the
latest in a tranche of research puporting to show
analgesic equivalence between the new COX-2
antagonists and older NSAIDS in a variety of settings.
These studies suggest that the improved side-effect
profile of COX-2 inhibitors justifies their higher cost as
compared to conventional non-selective NSAIDs.
Schumacher et al allowed patients on low dose aspirin,
allopurinol or colchicine to continue their medication
and be included in the study. The decision to allow
patients to take low dose aspirin is logical given the
increased CVS mortality seen in previous trials of
COX-2 antagonists. However somewhat confusingly
their protocol then specifically prevents patients taking
any other analgesics including aspirin during the study.
Presumably it was considered that low dose aspirin
(<=325 mg/day) did not count as an analgesic.
We have not been given the numbers of patients taking
low dose aspirin during the trial (although we are given
the numbers of patients on both allopurinol and
colchicine). This information is of importance when you
consider that aspirin is a selective, irreversible COX-1
antagonist. Hence for any patient on aspirin plus
indometacin the only additional analgesic effect of
indometacin is likely to be due to its COX-2 inhibition.
So in patients on low dose aspirin the comparison is
effectively between the COX-2 inhibition of etoricoxib vs
indometacin, which is likely to be similar. As this is a
no difference study the power of the study is crucial and
this may be lessened by the presence of patients
concomitantly taking aspirin. Given the close
association between gout and vascular disease the
issue of low dose aspirin deserves a closer inspection.
Competing interests: No competing interests
Re: Confounded low dose aspirin
In a rapid response to our article "Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis" Anthony E Pickering raised several issues regarding the study design which allowed patients to continue their therapy of low dose aspirin once enrolled in this trial. We have addressed the questions raised in our response below.
The analgesic and anti-inflammatory effects of low dose aspirin, although valid in some settings, is largely irrelevant in the context of an acute attack of gout that occurred while patients are taking low dose aspirin. The most important aspect of treating an acute attack of gout is to provide the maximum amount of an NSAID as quickly as possible. Low dose aspirin (<_325 mg="mg" does="does" not="not" approach="approach" the="the" levels="levels" that="that" would="would" be="be" required="required" to="to" treat="treat" rapid="rapid" inflammation="inflammation" and="and" excruciating="excruciating" pain.="pain." furthermore="furthermore" in="in" practice="practice" rheumatologists="rheumatologists" primary="primary" care="care" givers="givers" do="do" typically="typically" discontinue="discontinue" their="their" patients="patients" current="current" regimen="regimen" of="of" low="low" dose="dose" aspirin="aspirin" when="when" treating="treating" an="an" attack.="attack." lastly="lastly" this="this" study="study" suffered="suffered" acute="acute" gout="gout" attack="attack" while="while" on="on" by="by" definition="definition" exclusion="exclusion" criteria="criteria" were="were" therapy="therapy" chronically="chronically" so="so" response="response" treatment="treatment" can="can" attributed="attributed" aspirin.="aspirin." however="however" we="we" agree="agree" it="it" have="have" been="been" helpful="helpful" supply="supply" number="number" reader="reader" they="they" could="could" judge="judge" for="for" themselves="themselves" potential="potential" influence="influence" concomitant="concomitant" medication="medication" may="may" had.="had." only="only" _4="_4" _5.3="_5.3" _9="_9" _12.0="_12.0" etoricoxib="etoricoxib" indometacin="indometacin" groups="groups" respectively="respectively" taking="taking" throughout="throughout" study.="study." thus="thus" inclusion="inclusion" such="such" a="a" small="small" expected="expected" any="any" meaningful="meaningful" impact="impact" efficacy="efficacy" results="results" or="or" overall="overall" conclusions.="conclusions." p="p"/>In response, we have analyzed the results of the primary and all secondary endpoints excluding those patients who were on low dose aspirin. The results of this analysis including the primary endpoint and all secondary endpoints corroborate the robust and comparable treatment effects for etoricoxib and indometacin that were observed for the intention-to-treat population reported in the published study. The results are provided below.
The mean baseline values for the patients’ assessment of study joint pain (primary endpoint) were 2.88 units for etoricoxib and 2.99 units for indometacin for the intention-to-treat analysis and 2.85 units for etoricoxib and 2.94 units for indometacin when patients on low dose aspirin were excluded. The least-squares mean difference (95% confidence interval) between etoricoxib and indometacin for study joint pain change from baseline over Days 2 to 5 was 0.11 (-0.14, 0.35) for the intention-to-treat analysis and 0.11 (-0.16, 0.38) when patients on low dose aspirin were excluded. The least-squares mean difference (95% confidence interval) over Days 2 to 8 was 0.09 (-0.14, 0.33) for the intention-to-treat analysis and 0.07 (-0.19, 0.33) when patients on low dose aspirin were excluded. These data are consistent with and corroborate those of the published study and show that for both time periods the differences between treatments were within the prespecified boundaries for comparability. The data for the secondary endpoints are provided in the table below. Consistent with the primary endpoint, these data corroborate the conclusions of the published study.
Competing interests:
JAB and JN are employed by Merck and own shares of Merck common stock. HRS is on the Merck arthritis advisory board and has received speaking and consultancy fees from Merck and Pfizer.
Competing interests: Summary of secondary end points for days 2 to 8 Intention-to-treat population Excluding low dose aspirin users Treatment Group Least Squares Mean Change from Baseline (95% CI)** Least Squares Mean Difference From Indometacin (95% CI)** Least Squares Mean Change from Baseline (95% CI)** Least Squares Mean Difference From Indometacin (95% CI)** Tenderness of study joint (0 to 3 scale)*† Etoricoxib 120 mg(n/N=74/75) -1.76 (-1.91, -1.62) -0.01 (-0.22, 0.20) -1.74 (-1.89, -1.59) -0.02 (-0.23, 0.20) Indometacin 150 mg(n/N=73/75) -1.75 (-1.91, -1.60) NA -1.73 (-1.89, -1.56) NA Swelling of study joint (0 to 3 scale)*‡ Etoricoxib 120 mg(n/N=74/75) -1.45 (-1.61, -1.29) 0.00 (-0.22, 0.23) -1.41 (-1.58, -1.25) 0.00 (-0.24, 0.24) Indometacin 150 mg(n/N=73/75) -1.45 (-1.62,-1.28) NA -1.41 (-1.60,-1.23) NA Patients’ global assessment of response to treatment (0- to 4-Likert scale)§ Etoricoxib 120 mg(n/N=74/75) 1.42 (1.20, 1.65) 0.10 (-0.21, 0.41) 1.38 (1.15, 1.61) -0.01 0.34, 0.32) Indometacin 150 mg(n/N=72/75) 1.33 (1.10, 1.56) NA 1.39 (1.14, 1.64) NA Investigators’ global assessment of response to treatment (0- to 4-Likert scale)*¶ Etoricoxib 120 mg(n/75=74/75) 0.89 (0.70, 1.08) 0.01 (-0.25, 0.28) 0.88 (0.68, 1.08) -0.02 (-0.30, 0.27) Indometacin 150 mg(n/N=73/75) 0.88 (0.69, 1.08) NA 0.89 (0.68, 1.11) NA NA=not applicable; CI=confidence interval; n/N=total number of patients in analysis (n) versus total number of patients randomized to treatment group(N). * All investigator assessments throughout the study were carried out by the same physician for a given patient† 0=no pain, 1=patient states that there is pain, 2=patient states that there is pain and winces, 3=patient states that there is pain, winces, and withdraws.‡ 0=none, 1=palpable, 2=visible, 3=bulging beyond joint margins§ 4=poor, 3=fair, 2=good, 1=very good, 0=excellent¶ 4=none-no response, absence of drug effect, 3=poor-minimal response; unacceptable, 2=definite response, but could be better, 1=good-good response, but less than the best possible anticipated result, 0=excellent-best possible anticipated response, considering the severity of the gout attack.**Patient and investigator global assessments of response to treatment are least squares mean treatment values.