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Rostom A, Dube C, Lewin G. Use of Aspirin and NSAIDs to Prevent Colorectal Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Mar. (Evidence Syntheses, No. 45.)

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Use of Aspirin and NSAIDs to Prevent Colorectal Cancer [Internet].

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Appendix 5. Results: Harms Due to COX-2 Inhibitor Use (Including COX-2 Selective)

Fourteen systematic reviews investigated the harms due to COX-2 inh use (Evidence Table 3.3).

General

Six systematic reviews assessed the general harms associated with COX-2 inh use in the adult population.16 All six reviews included exclusively RCTs. The types of harms due COX-2 use relevant for this review were: all-cause of mortality, mortality due to harms and withdrawals due to harms.

All-cause mortality

All-cause mortality was reported in three reviews.1, 2, 6 Hooper et al. found no statistically significant difference between COX-2 inh (selective or specific) and other type of NSAIDs.1 For the less specific COX-2 inhs (etodolac, meloxicam, nabumetone or nimesulide) the RR was 0.68 (95% CI: 0.3–1.6) across 51 RCTs, while the 17 RCTS of COX-2 specific (celecoxib and refocoxib) showed a pooled RR of 1.02 (95% CI: 0.6–1.9).1 Garner et al. did not observe any death across three RCTs comparing celecoxib with either placebo or other NSAIDs2 and found no difference in mortality between rofecoxib (0.5%) and naproxen (0.4%) in the VIGOR trial (VIGOR: data from FDA 2001).6

Withdrawals due to harms

The withdrawals due to harms were reported in six reviews.16 Hooper et al. observed that there was no significant difference between COX-2 selective inhs and NSAIDs across 51 trials (RR: 0.93 [95% CI: 0.9–1.0]), whereas, the risk was reduced in the 17 RCTS comparing COX-2 specific inhs with NSAIDs, yet the heterogeneity test was significant for this result (pooled RR: 0.82 [95% CI: 0.7–0.9]).1 Deeks et al. found an increased risk of withdrawal due to harms in the celecoxib group compared with placebo in five RCTs (RR: 1.49 [95% CI: 1.15–1.92]), however, when the celecoxib group is compared with other NSAIDs the risk did not differ significantly (RR: 0.86 [95% CI: 0.72–1.04]) across eight RCTs.3 Garner et al. showed that there was no difference between celecoxib and placebo for this outcome in one trial.2 Edwards et al. observed no difference between valdecoxib and placebo (RR: 0.9 [95% CI: 0.7–1.3]), but valdecoxib use was associated with a lower risk of withdrawals due to harms when compared with other NSAIDs (RR: 0.6 [95% CI: 0.5–0.7]).4

Garner et al. showed significantly greater withdrawals due to harms with rofecoxib 12.5 mg (RR: 2.18 [95% CI: 1.34–3.55]) and 50 mg/day (RR: 2.04 [95% CI: 1.24–3.36]) when compared to placebo when used over 6–12 weeks.5 When rofecoxib (12.5 to 25 mg/day) was compared with diclofenac (150 mg/day), there were fewer withdrawals due to harms in both 12.5 mg and 25 mg/day (RR: 0.71 [0.52–0.97] and RR: 0.70 [0.51–0.95], respectively) in two 1-year trials.5 Nine trials were pooled comparing the withdrawals due to harms between celecoxib (200 mg/day) versus rofecoxib (25 mg/day), showing no differences (RR: 1.03 [0.77–1.39]).5

In another review, Garner et al. showed that there was no statistically significant difference between rofecoxib 5 mg (3%), 25 mg (3.2%), 50 mg (4.7%) and placebo (6.2%) based one trial,6 and no difference between rofecoxib and naproxen in another(RR: 1.02 [95% CI: 0.92–1.12]).6

In general COX-2 inh appear to be better tolerated than NSAIDs, but are associated with some adverse effects when compared with placebo.

CV harms

There were seven systematic reviews addressing the magnitude of CV harms due to COX-2 inh use in an adult population.2, 49 Six reviews included exclusively RCTs, while Jüni et al. also included observational studies such as cohort or case-control studies.9

The CV events reported across the systematic reviews were: death due to CV events, serious CV events (overall), acute MI, acute stroke, arterial hypertension, congestive heart failure, edema, and thrombotic events.

Three reviews reported the mortality due to CV events.2, 6, 9 Garner et al. reported that none of the trials had experienced deaths due to CV events in patients taking celecoxib or comparators,2 and no difference in CV mortality between rofecoxib and naproxen (0.2% both groups)in another trial.6 Jüni et al. found no significant difference between rofecoxib and other NSAIDs in nine RCTs [RR: 0.79 (95% CI: 0.29–2.19)].9

Overall serious CV events were reported in two reviews.8, 9 Jüni et al. found that the rofecoxib group had an increased risk of serious CV harms compared with standard NSAIDs (RR: 1.55 [95% CI: 1.05–2.29]).9 Mukherjee et al. also found an increased risk of events in the VIGOR trial (rofecoxib vs. naproxen) with a RR of 1.89 (95% CI: 1.03–3.45) in low-risk patients (not aspirin takers), while the high CV risk group (aspirin indicated patients) had a RR of 4.89 (95% CI: 1.41–16.88).8

Five reviews reported the risk of acute MI in patients taking COX-2 inh.46, 8, 9 Jüni et al. observed an increased risk of MI with rofecoxib versus control groups (RR: 2.24 [95% CI: 1.24–4.02]).9 Jüni et al. performed a stratified meta-analysis that showed the estimates of RR varied depending on whether rofecoxib had been compared with placebo (RR: 1.04 [0.34–3.12]), NSAIDs other than naproxen (RR: 1.55 [0.55–4.36]) or naproxen (RR: 2.93 [1.36–6.33]). High dose rofecoxib (50 mg/day) (RR: 2.83 [1.24–6.43]), as well as long-term use of at least 6 months (RR: 2.17 [1.03–4.59]) showed a significant increase in the risk of MI.9 Mukherjee et al. reported that there were 26/99 cases of MI in patients taking rofecoxib and 37/102 cases in patients taking celecoxib in the Adverse Event Reporting System in United States.8 Garner et al. reported the results of one large RCT (ADVANTAGE study),10 where 5/2,785 and 1/2,772 patients in the rofecoxib and naproxen groups, respectively, had an episode of MI (RR: 4.98 [95% CI: 0.58–42.57]).5 The statistically non significant result of this trial and the few events that occurred make drawing conclusions from this trial difficult. In another review, Garner et al. reported that there was an increased risk of MI with rofecoxib compared with naproxen from one trial (VIGOR), with a RR of 5.0 (95% CI: 1.5–13.2).6

Edwards et al. observed that there were 3/2733 (0.1%) cases of MI in the valdecoxib group compared with 11/1846 (0.6%) cases in the NSAID group in nine RCTs.4 This difference was statistically significant.4

Acute stroke was reported in four reviews.5, 6, 8, 9 Jüni et al. combined 11 RCTs and found no difference between rofecoxib and standard NSAIDs (RR: 1.02 [95% CI: 0.54–1.93]).9 Garner et al. likewise found no difference between rofecoxib and naproxen (RR: 0.08 [95% CI: 0.00–1.36])5in the ADVANTAGE study, or for total cerebrovascular events (RR: 1.37 [0.55–3.41]), ischemic stroke (RR: 1.12 [0.43–2.91]) and TIA (RR: 4.98 [0.24–103.77]) in the VIGOR study.6 Mukherjee et al. reported that there were 43/99 cases of stroke in patients taking rofecoxib, and 31/102 cases in patients taking celecoxib in the Adverse Event Reporting System in United States.8

Arterial hypertension was reported in four reviews.2, 57 Garner et al. found that there were similar rates of hypertension between three doses of rofecoxib and placebo in one review6 and another review reported that hypertension occurred in 4/236 (1%) patients taking celecoxib and 5/329 (2%) patients taking diclofenac in one RCT.2 Gomez Cerezo et al. reported that the patients included in the VIGOR trial using rofecoxib had an increased risk of withdrawal due to hypertension related adverse events compared with naproxen use (RR: 4.67 [95%CI: 1.93–11.28]).7 Garner et al. reported that there was no difference between rofecoxib and naproxen in the ADVANTAGE trial (RR: 1.22 [95% CI: 0.89–1.68]),5 and no difference between rofecoxib and nabumetone in the risk of hypertension (RR: 1.46 [95% CI: 0.53–4.12]) in three 6-week RCTs.5 There were no differences between rofecoxib and celecoxib in this outcome (RR: 3.51 [0.73–16.84]) in two trials.5

Gomez Cerezo et al. also reported that the risk of developing congestive heart failure in the rofecoxib group did not differ from the naproxen group in one large trial (VIGOR; RR: 2.11 [95% CI: 0.96–4.67]).7

The incidence of lower extremity edema was reported in five reviews.2, 47 Garner et al. showed that the incidence of peripheral edema was 1% to 2% in the celecoxib groups compared with none in the placebo groups across two trials.2 However, the incidence of edema in the naproxen group and high dose (400–800 mg/day) celecoxib groups was 2% across two trials.2 More patients experienced peripheral edema in the celecoxib group (11/236, 3%) compared with the diclofenac group (5/329, 2%) in one trial.2 Garner et al. (2004) observed a similar incidence of edema among rheumatoid arthritis patients receiving three doses of rofecoxib (5, 25 and 50 mg/day) and those taking placebo at 8 weeks.6 Gomez Cerezo et al. reported a nonsignificant risk between rofecoxib and naproxen in the incidence of withdrawals due to edema in the VIGOR trial (RR: 1.92 [95% CI: 0.98–3.75]).7 Garner et al. reported that there was no difference between rofecoxib and nabumetone from three, 6-week RCTs, in the risk of lower extremity edema (RR: 1.41 [95% CI: 0.72–2.77]), as well as from one, 6-week RCT, comparing the use of rofecoxib with diclofenac/misoprostol (RR: 1.39 [95% CI: 0.63–3.08]).5 However, there was a greater incidence of edema in the rofecoxib (25 mg/day) groups compared with celecoxib (200 mg/day) groups from four RCTs (RR: 1.77 [95% CI: 1.27–2.47]).5 Lastly, Edwards et al. reported that edema affected 2% of patients taking valdecoxib and NSAID, and that it occurred significantly more frequently than with placebo (NNH: 57, 39–103) across nine trials.4

In summary, knowledge of the CVS harms of COX-2 inh and NSAIDs is in state of flux. There was a signal of increased cardiovascular events with rofecoxib from the VIGOR trial, and suggestion based on the Juni meta-analysis that COX-2 inh may have similar rates of CVS harms as non-naproxen-non-ASA NSAIDs, but higher rates when compared with naproxen for some endpoints. The effect of co-administration of ASA and COX-2 inhs for CVS harms has not been fully studied.

Renal

Edwards et al. observed that valdecoxib had an increased risk of developing clinically significant renal events (defined as verified abnormal renal laboratory test results or clinical findings) compared with placebo (RR: 2.9 [95% CI: 1.4–5.7]), yet not compared with other NSAIDs (ibuprofen, diclofenac or naproxen) (RR: 0.7 [95% CI: 0.5–1.0]).4

GI harms

Twelve reviews addressed the GI harms with the COX-2 inh use.17, 1115

In general, the COX-2 inh harms data is of greater quality than those for ASA and non-ASA NSAIDs as a result of the greater emphasis put on manufacturers by regulatory agencies in recent years to conduct large and longer term RCTs. For the non-ASA NSAIDs, a single large clinical outcome study was conducted.16 Similarly designed large RCTs of clinically important ulcer complications such as POBs (perforation, obstruction or bleeding) have been conducted for the COX-2 inhs.1720 In addition to these trials, combined analyses studies including previously unpublished manufacturer data have also been published.13, 2123 These combined analyses studies are a cross between a meta-analysis and primary clinical data in that previously unpublished data and published data from very similar trials are pooled. Furthermore, multiple trials of endoscopic ulcer outcomes have also been published for the COX-2 inh compared with placebo, and to various non-ASA NSAIDs.24

The included systematic reviews of the GI safety of COX-2, therefore, encompass more or less the same body of evidence described above, with the major differences being the number of included studies (because of the date of publication of the systematic review) and the emphasis of the conclusions. The following COX-2 inhs were assessed in these systematic reviews: celecoxib;13, 11, 12, 25, 26 rofecoxib;1, 57, 11 valdecoxib;4, 13, 15 and meloxicam.1, 11, 14 Three systematic reviews considered more than one COX-2 inh.1, 7, 11

COX-2 inh compared with placebo. Six Reviews24, 6, 11, 13 found no statistically statistically significant difference in GI bleeding or ulceration between COX-2 inhs and placebo. In a review by Ascroft et al.,12 those patients taking celecoxib 200 mg/day did not have an increased risk of endoscopic ulcers compared with placebo, but those taking 400 mg/day were at increased risk (RR= 2.35; 95% CI: 1.02–5.38). Garner5found a statistically increased risk of total adverse events (RR=1.32; 95% CI: 1.11–1.56) and total GI events (one study, RR=3.39; 95% CI: 1.47–7.84) with rofecoxib compared with placebo at 6 weeks, but not at longer time periods or for single GI outcomes.

COX-2 inh compared with non-ASA NSAIDs. In general, COX-2 are associated with a significantly lower risk of endoscopically-detected ulcers, clinically significant POBs/PUBs (POB or symptomatic ulcer), and dyspeptic symptoms than with non-ASA NSAIDs when the later group is pooled to include the commonly studied agents (ibuprofen, diclofenac, and naproxen). Furthermore, since the systematic reviews included many of the same studies, the actual risk estimates are fairly consistent.

The RR of endoscopic ulcers with a COX-2 inh versus a non-ASA NSAID is close to 0.25 (i.e., a 75% RR reduction).13, 5, 6, 11, 12 The RR of POBs and PUBs each varied somewhat from about 0.40 to 0.60 (40%–60% RR reduction).14, 6, 7, 11, 13, 14 This latter result is driven by the COX-2 inh clinical outcome studies described above. COX-2 inhs also appear to be associated with a statistically lower RR for GI symptoms, such as dyspepsia.1, 3, 5, 11, 15

Specific COX-2 and specific Non-ASA NSAIDs. Celecoxib, rofecoxib and valdecoxib individually appear to have greater GI safety than naproxen, and ibuprofen with RRs of endoscopic ulcers and POBs similar to that reported above for the combined analyses.2, 3, 57, 11, 12 However, some systematic reviews, particularly those based on the results of the CLASS study,17 have suggested that celecoxib may not offer any advantage over diclofenac. In the CLASS trial there was no statistically significant difference in POBs between celecoxib and NSAIDs combined or celecoxib versus diclofenac. Celecoxib, however, appeared to be safer than ibuprofen.3, 5, 7, 11, 17 Rostom et al. also found no statistically significance difference in PUBs between COX-2 and diclofenac in a pooled analysis of six trials.11 Furthermore, the systematic reviews by Rostom11 and Ashcroft12 found no difference in endoscopic ulcers between celecoxib and diclofenac, though Ashcroft reports that in one 24-week study the RRR in favor of celecoxib over diclofenac reached statistical significance. Garner et al. reported similar findings for celecoxib versus diclofenac based on the CLASS study.2 The apparent safety of diclofenac in this setting may be explained by its greater COX-2 selectivity compared with other non-ASA NSAIDS.27

The GI safety of meloxicam has been assessed in three of the systematic reviews,1, 11, 14 although in the review by Hooper, meloxicam was pooled with etodolac, nabumetone, and nimesulide. If one only considers the two large meloxicam trials,19, 20 then there is no statistically significant difference in POBs or PUBs between meloxicam and the compared NSAIDs (piroxicam and diclofenac), even when these studies are pooled.1, 11, 14 However, the addition of data from combined analyses trials, efficacy and tolerability trials allows meloxicam to show a statistically significant reduction in PUBs compared with non-ASA NSAIDs1, 11, 14

Influence of coadministration of ASA with a COX-2 inhs. Three trials allowed assessment of the effects of the co-administration of ASA with a COX-2: the CLASS, and TARGET studies,17, 28 and the valdecoxib combined analysis.13 The results of all three trials found that among ASA users, the use of a COX-2 offers no GI safety advantage over the use of a standard non-ASA NSAID. In subgroup analyses of the CLASS study, celecoxib was superior to combined NSAIDs in patients not taking ASA, but not for those on celecoxib and ASA. The risk of ulcer complications in patients taking celecoxib and ASA was nearly four times that of those who were not taking ASA. Paradoxically, patients taking ibuprofen and low-dose ASA suffered fewer ulcer complications than patients taking either celecoxib or diclofenac and low-dose ASA.11, 17 Nearly identical findings were reported by Goldstein et al. in a combined analysis study of the safety of valdecoxib.13 In that study, valdecoxib users who were also taking ASA had a nine-fold greater risk of GI bleeding than those on valdecoxib alone. Goldstein also found that patients in the non-ASA NSAID arms of these studies who were also taking ASA did not have any further increased risk of GI bleeding.

Dose effect of COX-2 inhs. Rostom et al.11 analyzed the COX-2 data by dose. In this systematic review, low-dose COX-2 selective NSAIDs were defined as celecoxib 200 mg bid or less, rofecoxib 25 mg daily or less, and meloxicam 7.5 mg daily. There were no statistically significant differences between low dose (seven studies) and high dose (three studies) COX-2 compared with non-ASA NSAIDs for the outcome of endoscopic ulcer,11 Ashcroft found no difference in the risk of endoscopic ulcers between celecoxib 200 mg and 400 mg per day.12 Garner, in a combined analysis of two studies, found a greater risk of endoscopic ulcers >5mm with rofecoxib 50 mg/day compared with 25 mg/day (RR=2.48; 95% CI: 1.21–5.11), but not for endoscopic ulcers >3mm or for the more frequent gastric ulcers.5 Goldstein likewise found no differences in ulcer complications across doses of valedcoxib ranging from 5 mg to 80 mg per day.13 The apparent GI safety of the COX-2 with higher doses may be in part explained by their relatively flat COX-2 inhibition curve in the range of doses that can be used clinically.27

In summary, COX-2 inhs offer greater GI safety than most non-ASA NSAIDs. The safety advantage over non-ASA NSAIDs appears to disappear when COX-2 inh are used with ASA.

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