Results

Celecoxib

Two systematic reviews included in the original CER evaluated the efficacy of celecoxib versus nonselective NSAIDs.^{50, 51} We identified two fair-quality head-to-head trials of celecoxib versus diclofenac (n=925 and n=249) published since the original CER (Appendix H).^{52, 53}

A good-quality systematic review (published in 2002) funded by the makers of celecoxib found similar effects on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores associated with celecoxib and nonselective NSAIDs based on data from published and unpublished randomized trials of at least 12 weeks’ duration in patients with either osteoarthritis (OA) or rheumatoid arthritis (RA).⁵⁰ A more recent systematic review (published in 2005) with access to all unpublished manufacturer-held clinical trial reports found celecoxib at doses of 200–400 mg associated with slightly higher rates of withdrawals due to lack of efficacy compared to nonselective NSAIDs (RR 1.1; 95% CI 1.0, 1.2), based on data from 31 primarily short-term (≤12 weeks) trials.⁵¹

The two largest head-to-head trials of celecoxib versus nonselective NSAIDs are the Celecoxib Long-term Arthritis Safety Study (CLASS)⁵⁴ and the Successive Celecoxib Efficacy and Safety Study-1 (SUCCESS-1).⁵⁵ Both systematic reviews included CLASS (n=7,968), a pivotal, long-term (6 to 13 months) trial of celecoxib versus the nonselective NSAIDs ibuprofen or diclofenac for rheumatoid and osteoarthritis.⁵⁴ The nonselective NSAIDs were associated with a slightly higher (but statistically significant) likelihood of withdrawal due to lack of efficacy compared to celecoxib (15% vs. 13%, p=0.005). CLASS focused on assessment of adverse events rather than efficacy, and other efficacy results were not reported. The Moore et al. systematic review⁵¹ included the large (n=13,274), Successive Celecoxib Efficacy and Safety Study (SUCCESS-1), which found no clinically meaningful (and mostly statistically nonsignificant) differences after 12 weeks in efficacy (pain, global assessment of arthritis, or WOMAC total score) between celecoxib 100 mg or 200 mg twice daily and the nonselective NSAIDs diclofenac and naproxen in patients with osteoarthritis.⁵⁵ Withdrawals due to lack of efficacy were not reported.

A new, fair-quality trial (high loss to followup) found no differences between celecoxib 200 mg once daily and diclofenac 50 mg twice daily in pain scores, global assessment of arthritis, or patient satisfaction through 52 weeks of followup in older (≥60 years) patients (n=925) with osteoarthritis.⁵² Withdrawals due to adverse events were slightly less frequent with celecoxib compared with diclofenac, but the difference was not statistically significant (27% vs. 31%, RR 0.87, 95% CI 0.71–1.1). Another new, fair-quality trial (high loss to followup, allocation concealment method not described, failure to report intention-to-treat analysis) reported results inconsistent with other trials.⁵³ It failed to demonstrate noninferiority of celecoxib 200 mg compared to diclofenac 50 mg three times daily on pain at 6 weeks (mean difference between drugs in change from baseline 12 mm on a 0 to 100 visual analogue scale (VAS), 95% CI 5.8 to 18) or 12 weeks (10 mm, 95% CI 2.8 to 17) in patients with hip osteoarthritis requiring joint replacement surgery. Withdrawals due to lack of efficacy were similar (13 percent vs. 11 percent).

Partially Selective NSAIDs

Three systematic reviews included in the original CER evaluated the efficacy of the partially selective NSAIDs etodolac or nabumetone versus nonselective NSAIDs.^{9, 56, 57} One new, good-quality systematic review evaluated comparative efficacy of the partially selective NSAIDs for osteoarthritis or rheumatoid arthritis (Appendix H).⁵⁸ We identified no new head-to-head trials of partially selective NSAIDs versus nonselective NSAIDs published since the original CER.

Eleven randomized, double-blinded trials of meloxicam 7.5 mg, 15 mg, or 25 mg versus other NSAIDs for osteoarthritis found no clear or consistent differences in efficacy.^59–69 In two of the trials, meloxicam was associated with a greater likelihood of withdrawal due to lack of efficacy than nonselective NSAIDs.^{63, 68} The new systematic review, which included trials of patients with osteoarthritis or rheumatoid arthritis, found meloxicam associated with lower efficacy compared to nonselective NSAIDs for pain (difference 1.7 points on a 10-point VAS pain scale, 95% CI 0.8 to 2.7) and withdrawals due to lack of efficacy (RR 1.5, 95% CI 1.2 to 1.7).⁵⁸

The original CER included several good-quality Cochrane systematic reviews of randomized trials that found no difference between etodolac and various nonselective NSAIDs for OA of the hip (trials published through 1994),⁷⁰ back (through 1998),⁹ or knee (through 1997).⁵⁷ In seven trials published after or not included in the Cochrane reviews, there were also no differences between sustained-release etodolac and diclofenac⁷¹ or tenoxicam;⁷² or between standard-formulation etodolac and piroxicam (2 trials^{73, 74}), naproxen (2 trials^{75, 76}), or nimesulide⁷⁷ for OA of the knee, hip, or foot. The new systematic review found no differences between etodolac and various nonselective NSAIDs for pain (mean difference 2.1, 95% CI −2.1 to 6.2) or withdrawals due to lack of efficacy (RR 1.0, 95% CI 0.85 to 1.2) in patients with osteoarthritis or rheumatoid arthritis.⁵⁸

The Cochrane review of NSAIDs for knee osteoarthritis found nabumetone similar in efficacy to the nonselective NSAIDs diclofenac SR⁷⁸ and etodolac⁷⁹ in two 4-week trials.⁵⁷

Nonselective NSAIDs

The original CER included several good-quality systematic reviews by the Cochrane Collaboration of trials that compared various nonselective NSAIDs for OA of the hip (trials published through 1994),⁷⁰ back (through 1998),⁹ or knee (through 1997).⁵⁷ These reviews found no clear differences in efficacy between non-aspirin, primarily nonselective NSAIDs. We identified no new head-to-head trials comparing efficacy of one non-aspirin, nonselective NSAID versus another. The large SUCCESS-1 trial included diclofenac and naproxen arms, but only reported combined efficacy results for these two nonselective NSAIDs.⁵⁵

Aspirin or Salsalate

We identified no new head-to-head trials comparing efficacy of aspirin or salsalate versus other NSAIDs. A head-to-head trial included in the original CER found salsalate 3 g once daily and aspirin 3.6 g once daily associated with similar efficacy in patients with OA after 2 weeks of treatment.⁸⁰

Randomized Controlled Trials

Randomized Controlled Trials

Other NSAIDs

One systematic review included in the original CER evaluated risk of serious CV events associated with nonselective NSAIDs.¹²¹ We identified one new systematic review¹¹⁵ Two trials included in the original CER and not included in the systematic review also reported serious CV events in patients prescribed naproxen.^{55, 122}

A new, good-quality systematic review by Trelle and colleagues of 31 trials (with at least two arms with at least 100 patient-years of followup) compared CV risks associated with various nonselective NSAIDs, based on a network analysis.¹¹⁵ It found ibuprofen associated with increased risk of composite cardiovascular outcomes (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) compared with placebo (RR 2.3, 95% CI 1.1 to 4.9) and diclofenac associated with a trend towards increased risk (RR 1.6, 95% CI 0.85 to 3.0). Among the nonselective NSAIDs, with respect to specific CV outcomes, diclofenac was associated with the highest risk of stroke (RR 2.9, 95% CI 1.1 to 8.4) and cardiovascular death (RR 4.0, 95% CI 1.5 to 13). Naproxen was associated with only a slight, nonsignificant trend toward increased risk (RR 1.2, 95% CI 0.78 to 1.9). There were no statistically significant differences in risk of composite CV outcomes between naproxen, ibuprofen, and diclofenac.

A fair-quality systematic review included in the original CER by Kearney and colleagues of 91 trials (mostly ranging from 4 to 13 weeks in duration) evaluated risks associated with any nonselective NSAID (33,260 person-years of exposure) compared to any COX-2 selective NSAID (23,325 person-years of exposure).¹²¹ Most of the trials evaluated naproxen (42 trials), ibuprofen (24 trials), and diclofenac (26 trials); only 7 evaluated other nonselective NSAIDs. Generalizability to usual practice could be limited because the majority of the trials evaluated higher than standard doses of NSAIDs. Much of the data regarding CV event rates were obtained by requesting unpublished data from trial sponsors.

Table 6 shows estimates of risk for different CV outcomes with COX-2 inhibitors relative to nonselective NSAIDs. Risk of myocardial infarction was similar with COX-2 inhibitors and nonnaproxen NSAIDs, but about twofold as great for COX-2 inhibitors compared with naproxen (0.6% or 99/16360 vs. 0.3% or 30/10,978, RR 2.0, 95% CI 1.4 to 3.0). This is equivalent to about 1 additional myocardial infarction for every 300 patients treated for 1 year with a COX-2 inhibitor instead of naproxen. COX-2 inhibitor use was also associated with a lower risk of stroke relative to nonnaproxen NSAIDs (RR 0.62, 95% CI 0.41 to 0.95). In subgroup analyses of specific nonselective NSAIDs (ibuprofen, diclofenac, other nonselective NSAIDs), the difference in stroke risk was only observed with diclofenac, which was usually evaluated at high doses (RR 0.48, 95% CI 0.27 to 0.83). There was insufficient data to analyze the effects of lower doses on estimates of risk.

Kearney et al. found insufficient data to directly estimate risks of nonselective NSAIDs from placebo-controlled trials. Indirect analyses (based on trials of nonselective NSAIDs versus COX-2 inhibitors and trials of COX-2 inhibitors vs. placebo) suggested an increased risk of vascular events with ibuprofen (RR 1.5, 95% CI 0.96 to 2.4) and diclofenac (RR 1.6, 95% CI 1.1 to 2.4) relative to placebo, but not with naproxen (RR 0.92, 95% CI 0.67 to 1.3). However, indirect analyses should be interpreted with caution because they can give discrepant results compared to head-to-head comparisons.¹²³

The Kearney meta-analysis did not include results of the large SUCCESS-1 trial, which reported 0.61 MIs/100 patient-years with naproxen (n=905), and no cases of MI in diclofenac users (n=3489).⁵⁵ It also didn’t include the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT), which was terminated early in December 2004 because of an “apparent increase in CV and cerebrovascular events among the participants taking naproxen when compared with those on placebo.”¹²⁴ Results from ADAPT showed a nonsignificant increased in risk of CV deaths (HR 1.5, 95% CI 0.30 to 7.3), myocardial infarction (HR 1.5, 95% CI 0.69 to 3.2), or stroke (HR 2.1, 95% CI 0.81 to 5.6).¹²² Naproxen was associated with an increased risk based on the composite outcome of CV death, myocardial infarction, stroke, congestive heart failure, or transient ischemic attack (HR 1.6, 95% CI 1.0 to 2.6). The decision to terminate ADAPT has been criticized because rigorous stopping protocols were not used, the increased risk associated with naproxen for individual and most composite CV outcomes did not reach statistical significance, the events were not adjudicated, and the number of events was small.¹²⁵

Aspirin and Salsalate

Aspirin is known to be protective against occlusive vascular events because of its irreversible antiplatelet effects. In a collaborative meta-analysis of infidel patient data from 22 randomized trials (over 110,000 participants), lower doses of aspirin (primarily less than 325 mg daily) were associated with decreased risk of serious vascular events when given for primary prevention (0.51% aspirin vs. 0.57% control per year, p=0.0001) or secondary prevention (6.7% vs. 8.2%, p<0.0001).⁹⁶ The populations evaluated in these trials probably varied substantially from trials of patients with arthritis.

Observational Studies

Three systematic reviews evaluated CV risk associated with various NSAIDs.^126–128 Two were included in the original CER and focused on risks associated with naproxen.^{126, 127} The third was a new, good-quality systematic review of CV risk (primarily myocardial infarction) from 23 observational studies that was published too late to be included in the original CER, though results were summarized in a brief addendum (Appendix H).¹²⁸ We also identified four large observational studies not included in the original CER.^{108, 129–131}

The new systematic review included a total of 23 observational studies (16 case-control and 7 cohort studies).¹²⁸ It found diclofenac associated with the highest risk, followed by indomethacin and meloxicam (Table 7). Celecoxib, naproxen, piroxicam, and ibuprofen were not associated with increased risks. For all NSAIDs, increases in risk were modest (RR <1.5), and all of the main analyses were characterized by substantial between-study heterogeneity.

Nineteen large observational studies (case-control studies with >1000 cases or cohort studies with >100,000 subjects) evaluated risk of CV events associated with various NSAIDs (Table 8, Appendix H).^{108, 129–146} All of these studies except for four^{108, 129–131} were included in the original CER. Seven studies^{108, 129–132, 141, 146} not included in the systematic review of observational studies.¹²⁸ Six studies used a cohort design^{108, 130, 131, 140, 146, 147} and the remainder a case-control (or nested case-control) design. Three studies evaluated the UK General Practice Research Database^{133, 134, 143} and three evaluated the same Canadian (Quebec) database.^{108, 130, 141} Only one study was rated good quality,¹³⁹ the remainder were rated fair quality. The most common methodological shortcoming in the fair-quality case-control studies was failure to report the proportion of patients who met inclusion criteria who were excluded from the study. The most common methodological shortcomings in the fair-quality cohort studies were unclear blinding status of outcomes assessors and data analysts, and failure to report attrition from a defined inception cohort. Interpretation of the studies was complicated by the use of different study designs, adjustment for different numbers and types of confounders, and evaluation of different populations and outcomes.

Sixteen observational studies evaluated risk of serious CV events (primarily myocardial infarction) associated with celecoxib.^{108, 129–132, 135–140, 145–149} Three studies found celecoxib associated with similar risk of CV events compared to naproxen, ibuprofen, or diclofenac.^{130, 145, 146} A fourth study found ibuprofen (OR 1.3, 95% CI 1.0 to 1.6) and naproxen (OR 1.4, 95% CI 1.1 to 1.8) associated with a higher risk of acute MI requiring admission or sudden cardiac death than celecoxib.¹³⁵ Twelve studies found no increased risk of serious CV events with celecoxib relative to nonuse of NSAIDs.^{108, 129, 131, 135, 136, 138–140, 145–148} Three studies found current (RR 1.6, 95% CI 1.2 to 2.0),¹³² new (RR 2.1, 95% CI 1.4 to 3.1),¹³⁷ or any (HR 1.5, 95% CI 0.99 to 2.2)¹⁴⁹ use of celecoxib associated with increased risk compared to nonuse of NSAIDs. In these studies, the increased MI risk was either time-¹³⁷ or dose-dependent.¹³²

The nonselective NSAID naproxen has received additional scrutiny since the VIGOR trial¹⁷ showed an increased risk of CV events with rofecoxib versus naproxen, due to the hypothesis that naproxen might be protective against myocardial infarction. In addition, a systematic review¹²¹ of randomized trials (described earlier) found that naproxen was not associated with the same increased in CV risk as other nonselective and selective NSAIDs. In addition to the new systematic review of observational studies described above (which found a neutral effect of naproxen on CV risk),¹²⁸ two systematic reviews included in the original CER specifically focused on CV risks associated with naproxen.^{126, 127} The first, a meta-analysis of 11 observational studies of naproxen (four based on the General Practice Research Database) found naproxen associated with a small cardioprotective effect (OR 0.86, 95% CI 0.75 to 0.99), with Merck-funded studies reporting larger effect sizes.¹²⁷ Nine observational studies published after this systematic review showed no cardioprotective effect associated with naproxen,^{108, 129, 132, 135–137, 139, 148, 149} though one other study showed a modest protective effect (HR 0.79, 95% CI 0.67 to 0.93).¹³¹ An FDA review included in the original CER concluded no cardioprotective effect of naproxen after taking into account various methodological issues.¹²⁶

Large observational studies found no other nonselective NSAID consistently associated with increased risk of CV events compared to nonuse of NSAIDs.^{129, 131–137, 139, 140, 142–144} For example, ibuprofen was associated with a modest increased risk (OR 1.4, 95% CI 1.3 to 1.6 and OR 1.2, 95% CI 1.1 to 1.4) of serious CV events compared to nonuse of NSAIDs in two^{129, 136} studies, but no increased risk in nine others.^{131–135, 143, 144, 147, 149}

Partially selective NSAIDs have not been well studied in large observational studies. Three studies found no increased risk of serious CV events with meloxicam compared to nonuse.^{129, 134, 139} One study found no increased risk of acute myocardial infarction with use of etodolac or nabumetone versus nonuse of NSAIDs, but estimates were imprecise.¹³³

In April 2005, after reviewing the available observational data, the FDA issued a Public Health Advisory stating, “Long-term controlled clinical trials have not been conducted with most of these (nonselective) NSAIDs. However, the available data suggest that use of these drugs may increase CV risk. It is very difficult to draw conclusions about the relative CV risk among the COX-2 selective and nonselective NSAIDs with the data available. All sponsors of nonselective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of available controlled clinical trial databases pertaining to their NSAID product(s) to which they have access to further evaluate the potential for increased CV risk.”¹⁵⁰ The FDA also required labeling changes to both prescription and nonprescription nonselective NSAIDs warning about potential CV risks.

Mortality

We identified no new studies evaluating mortality associated with different NSAIDs. Large clinical trials included in the original CER did not show differences in mortality between different NSAIDs.^{54, 152} In CLASS, mortality rates were 0.47%, 0.37%, and 0.45% for celecoxib, diclofenac, and ibuprofen, respectively.⁸⁴ In SUCCESS-1, 5 deaths (0.06 percent) were observed after 12 weeks in the celecoxib group and 5 (0.11 percent) in the nonselective NSAIDs group.⁵⁵ A meta-analysis that included unpublished company clinical trial data (including CLASS and SUCCESS-1) found no significant difference in rates of death in patients randomized to celecoxib compared with nonselective NSAIDs, though there were few events (0.03% or 6/18,325 in the celecoxib arms vs. 0.11% or 14/12,685 in the NSAID arms).⁵¹

One retrospective cohort study of Saskatchewan health-services databases that followed patients from 6 months following prescription until death found nabumetone associated with significantly lower rates of all-cause mortality compared with diclofenac (OR 2.0; 95% CI 1.2 to 3.1) and naproxen (OR 3.0, 95% CI 1.9 to 4.6).¹⁵³ However, we found no other studies that replicated this finding.

Hypertension, CHF, Edema, and Renal Function

Six systematic reviews or meta-analyses included in the original CER evaluated comparative risks of hypertension, CHF, edema, and renal function associated with various NSAIDs.^{19, 51, 110, 154–156} A seventh systematic review was published too late to be fully included in the original CER, but described in an appendix.¹⁵⁷ It was rated fair quality because it did not assess the quality of included studies. Two new observational studies evaluated risk of congestive heart failure in high risk patients.¹⁵⁸

All NSAIDs appear to be associated with increases in blood pressure. However, evidence regarding differential effects of specific NSAIDs is somewhat conflicting. One meta-analysis included in the original CER found that nonselective NSAIDs raised mean blood pressure by an average of about 5.0 mm Hg (95% CI 1.2 to 8.7).¹⁵⁴ Piroxicam produced the most marked elevation in blood pressure compared to placebo. In head-to-head trials, there were no significant differences between indomethacin and sulindac (10 trials), indomethacin and salicylate (1 trial), diclofenac and sulindac (1 trial), ibuprofen and sulindac (1 trial), and naproxen and sulindac (3 trials). Another meta-analysis found that piroxicam and ibuprofen had negligible effects on blood pressure, and that indomethacin and naproxen were associated with the largest increases.¹⁵⁵ In both meta-analyses, aspirin and sulindac were associated with minimal hypertensive affect. More than half of the published NSAID trials did not report hypertension rates as an outcome.¹⁵⁵

Several meta-analyses of celecoxib included in the original CER found no increased risk of hypertension compared to nonselective NSAIDs.^{19, 51, 110} A fair-quality meta-analysis found celecoxib (dose not specified) not associated with an increased risk of hypertension compared to either placebo (RR 0.81, 95% CI 0.13 to 5.21) or nonselective NSAIDs (RR 0.82, 95% CI 0.68 to 1.00).¹⁹ A Pfizer-funded meta-analysis submitted to the FDA found an increased risk of developing hypertension with celecoxib at any dose compared to placebo (1.1% vs. 0.7%, p=0.02), though the risk was lower than for nonselective NSAIDs (1.5% vs. 2.0%, p=0.002).¹¹⁰ A third meta-analysis, funded in part by the manufacturer, reported similar findings for risk of hypertension (celecoxib vs. nonselective NSAID, RR 1.1, 95% CI 0.90 to 1.3).⁵¹ The fourth meta-analysis, which was included as an appendix in the original CER, found celecoxib associated with slightly lower risk of hypertension (RR 0.83, 95% CI 0.71 to 0.97) compared with control treatments (placebo, other NSAID, or mixed/other).¹⁵⁷ Most of the trials included in the meta-analyses were short-term and only one meta-analysis⁵¹ evaluated the quality of the trials.

Results from large trials of celecoxib are mostly consistent with the meta-analyses. In CLASS (median duration of followup 9 months), celecoxib was associated with a similar rate of hypertension (new-onset and aggravated preexisting) compared with diclofenac (2.7 percent vs. 2.6 percent), and a lower rate compared with ibuprofen (2.7 percent vs. 4.2 percent).¹¹⁷ In the shorter-term (12 weeks) SUCCESS-I trial (N=13,274), rates of hypertension were similar with celecoxib 100 or 200 mg twice a day compared with either diclofenac or naproxen (RR 0.86, 95% CI 0.62 to 1.20).⁵⁵ The APC polyp prevention trial found celecoxib associated with greater systolic blood pressure elevations compared to placebo at 1 and 3 years at either 200 mg twice daily (2.0 mm Hg at 1 year and 2.6 mm Hg at 3 years) and 400 mg twice daily (2.9 mm Hg at 1 year and 5.2 mm Hg at 3 years).¹²⁰ On the other hand, the PreSAP polyp prevention trial found no difference in systolic blood pressure increases between celecoxib 400 mg once daily and placebo.¹²⁰

With regard to renal dysfunction, it is unclear whether COX-2 selective NSAIDs as a class are associated with clinically important differences in risk compared to nonselective NSAIDs. A systematic review included in the original CER of five small (sample size range 15 to 67), short-term (28 days or less) trials found that COX-2 selective NSAIDs had similar effects on glomerular filtration rate and creatinine clearance compared to nonselective NSAIDs in three trials, and were modestly superior in two.¹⁵⁶ The clinical effects of the modest differences observed in the latter two trials were unclear. Another systematic review found no difference in risk of creatinine increase greater than 1.3 times the upper limit of normal with celecoxib at 200 to 400 mg compared with nonselective NSAIDs (RR 0.78, 95% CI 0.46 to 1.3).⁵¹ CLASS showed no differences in the risk of experiencing an increase in serum creatinine >1.0 mg/dl with celecoxib (0.2 percent), diclofenac (0.1 percent), or ibuprofen (0.2 percent), though the nonselective NSAIDs were associated with slightly greater increases in serum creatinine, particularly in patients with prerenal azotemia at baseline.¹⁵⁹ A systematic review of randomized trials included as an appendix in the original CER found celecoxib associated with lower risk of renal dysfunction (RR 0.61, 95% CI 0.40 to 0.94) compared to control treatments (placebo, other NSAID, or mixed/other), but no difference for composite renal events (RR 0.97, 95% CI 0.84 to 1.1).¹⁵⁷

Two systematic reviews of randomized controlled trials included in the original CER found no clear difference between celecoxib and nonselective NSAIDs in risk of heart failure. In one systematic review, heart failure was more frequent with celecoxib than with placebo (13 of 8,405 vs. 1 of 4,057, p=0.05), though not compared with nonselective NSAIDs (0.1% vs. 0.2%, p=0.06).¹¹⁰ A second meta-analysis also found no significant difference between celecoxib and nonselective NSAIDs in risk of heart failure (RR 0.70, 95% CI 0.43 to 1.1).⁵¹ Similar results were observed in large trials of celecoxib. In CLASS, CHF rates were similar with celecoxib versus ibuprofen or diclofenac (0.3 percent vs. 0.3 percent).¹¹⁷, and withdrawals due to heart failure rare with all three NSAIDs (0.1% vs. <0.1% vs. 0.3%).¹⁵⁹ The APC polyp prevention trial found no difference in rates of heart failure between celecoxib versus placebo, though event rates were low (five cases of heart failure among 1,356 subjects).¹¹⁹

The risks of hypertension and heart failure with celecoxib and nonselective NSAIDs were evaluated in several observational studies. A new Danish cohort study of patients who had been hospitalized for congestive heart failure found use of celecoxib, ibuprofen, diclofenac, or naproxen at any dose associated with similar risk of hospitalization due to congestive heart failure (HR estimates ranged from 1.2 to 1.4), though celecoxib and diclofenac were associated with greater risk of death (HR 1.8, 95% CI 1.6 to 1.9 and HR 2.1, 95% CI 2.0 to 2.2, respectively) compared with ibuprofen and naproxen (HR 1.3, 95% CI 1.2 to 1.4 and HR 1.2, 95% CI 1.1 to 1.4, respectively).¹⁶⁰ A new nested case-control study found indomethacin associated with increased risk of heart failure compared to celecoxib (OR 2.0, 95% CI 1.2–3.6) in patients older than 66 years recently hospitalized for heart failure.¹⁵⁸ There was no difference in risk of heart failure between other nonselective NSAIDs (diclofenac [OR 0.82, 95% CI 0.51 to 1.3] and ibuprofen [OR 1.5, 0.66 to 3.2]) or acetaminophen (OR 1.2, 95% CI 0.92 to 1.4) relative to celecoxib. A retrospective cohort study included in the original CER based on the same Canadian database found nonselective NSAIDs associated with an increased risk of death (HR 1.5, 95% CI 1.2 to 2.0), recurrent heart failure (HR 1.2, 95% CI 0.92 to 1.6), or either (HR 1.3, 95% CI 1.0 to 1.6) in similarly high risk patients.¹⁶¹ Another retrospective cohort study included in the original CER found nonselective NSAIDs (RR 1.4, 95% CI 1.0 to 1.9) but not celecoxib (RR 1.0, 95% CI 0.8 to 1.3) associated with increased risk of heart failure admission compared to nonuse.¹⁶² A case-control study based on data from the General Practice Research Database found nonselective NSAIDs associated with an increased risk of newly diagnosed heart failure compared to nonuse of NSAIDs (RR 1.6, 95% CI 1.2 to 2.1).¹⁶³

A fair-quality systematic review included as an appendix in the original CER found no difference between celecoxib and controls (placebo, other NSAIDs, or mixed/other) in risk of arrhythmia, but the number of events was small (RR 0.84, 95% CI 0.45 to 1.6) and most trials didn’t report arrhythmias.¹⁵⁷

Hepatotoxicity

One systematic review¹⁶⁴ included in the original CER and one new meta-analysis¹⁶⁵ evaluated randomized controlled trials reporting hepatotoxicity associated with various NSAIDs. Another systematic review included in the original CER evaluated observational studies.¹⁶⁶ We identified one new randomized controlled trial of celecoxib versus diclofenac that reported rates of hepatic adverse events,⁵² and a report of hepatotoxicity from the diclofenac arm of a large randomized trial.¹⁶⁷

The new meta-analysis included 41 randomized trials involving celecoxib.¹⁶⁵ It found risk of hepatobiliary abnormalities (clinical or laboratory) similar for celecoxib (276/24933 or 1.1 percent), ibuprofen (38/2484 or 1.5%, p=0.06 vs. celecoxib), and placebo (36/4057 or 0.89%, p=0.21 vs. celecoxib); slightly lower rate for naproxen (0.68%, p=0.03 vs. celecoxib); and slightly higher for diclofenac (324/2618 or 4.24%, p<0.0001 vs. celecoxib). No patient randomized to an NSAID met Hay’s rule (elevation of alanine aminotransferase ≥3 times the upper limit of normal with an elevation of bilirubin ≥2 times the upper limit of normal), and no cases of liver failure or drug-related liver transplant were reported. The rate of alanine aminotransferase (ALT) abnormalities was higher with diclofenac (78/1000 patient-years) compared with the other NSAIDs or placebo (16 to 28/1000 patient-years). Four deaths occurred (2 in patients randomized to celecoxib, 1 naproxen, and 1 diclofenac), but none were considered related to drug treatment. A systematic review included in the original CER reported similar findings.¹⁶⁴ Based on 67 published articles and 65 studies accessible from the FDA archives, it found diclofenac (3.6%, 95% CI 3.1% to 4.0%) associated with higher rates of aminotransferase elevations greater than 3 times the upper limit of normal compared with placebo (0.29%; 95% CI 0.17% to 0.51%) and other NSAIDs (all ≤ 0.43 percent), and a higher rate of liver-related discontinuations compared to placebo (2.2%, 95% CI 1.8 to 2.6). Serious complications related to liver toxicity were rare: only one liver-related hospitalization (among 37,671 patients) and death (among 51,942 patients) occurred in a patient on naproxen in a trial of rofecoxib versus naproxen. Data from the diclofenac arm (n=17,289) of a randomized trial showed similar results.¹⁶⁷ The rate of aminotransferase elevation greater than three times the upper limit of normal was 3.1 percent, with four cases of liver-related hospitalizations (0.023 percent) and no cases of liver failure, death, or transplant.

Large trials that have evaluated diclofenac also suggested an increased risk of hepatotoxicity compared to other NSAIDs. In CLASS, celecoxib was associated with a lower risk of elevation in serum ALT (0.6 percent vs. 2.2 percent), serum AST (0.5 percent vs. 1.8 percent), and withdrawals due to hepatic enzyme elevations (<0.1 percent vs. 1.2 percent) compared to diclofenac or ibuprofen.⁵⁴ In SUCCESS-1, rates of increase in ALT levels were 0.5 percent with celecoxib versus 1.3 percent with diclofenac or naproxen (p<0.001).⁵⁵ A smaller (n=916), new trial comparing celecoxib versus diclofenac also found a lower risk of hepatic function abnormalities with celecoxib compared to diclofenac (0.6 percent vs. 3.5 percent).⁵²

A systematic review of seven population-based epidemiological studies found a similarly low risk of serious hepatic toxicity associated with NSAIDs.¹⁶⁶ In those studies, the excess risk of liver injury associated with current NSAIDs ranged from 4.8 to 8.6/100,000 person-years of exposure compared with past use. There were zero deaths from liver injury associated with NSAIDs in more than 396,392 patient-years of exposure. A recent cohort study from Italy found that nimesulide, an NSAID not available in the United States, was associated with a higher incidence of serious liver injury compared with other NSAIDs.¹⁶⁸ None of the other NSAIDs, including celecoxib, were associated with an increased risk of serious liver injury. An earlier review of five population-based studies found sulindac associated with a five- to tenfold higher incidence of hepatic injury compared with other NSAIDs.¹⁶⁹ Diclofenac was associated with higher rates of aminotransferase elevations compared with users of other NSAIDs, but not with a higher incidence of serious liver disease.

Celecoxib

Two systematic reviews^{50, 51} included in the original CER and one new systematic review⁵⁸ evaluated the relative tolerability of celecoxib compared to nonselective NSAIDs (Table 9). We also identified one new pooled analysis of randomized trials from the Pfizer registry,¹⁷⁰ one randomized trial not included in the original CER,⁵² and one pooled analysis of three similarly designed trials.⁸²

The new systematic review found no differences between celecoxib and nonselective NSAIDs in the risk of any adverse event (RR 0.96, 95% CI 0.91 to 1.0), GI adverse events (RR 0.90, 95% CI 0.78 to 1.0), or withdrawals due to adverse events (RR 0.86, 95% CI 0.73 to 1.0).⁵⁸ However, celecoxib was associated with a lower likelihood of withdrawals due to GI adverse events (RR 0.45, 95% CI 0.35 to 0.56). A systematic review included in the original CER reported found celecoxib associated with decreased risk of withdrawal due to adverse events (RR 0.86, 95% CI 0.81 to 0.91), withdrawal due to GI adverse events (RR 0.75, 95% CI 0.70 to 0.80), or any GI adverse event (RR 0.85, 95% CI 0.82 to 0.88).⁵¹ The risk of serious adverse events (RR 1.0, 95% CI 0.91 to 1.2) and any adverse event (RR 0.96, 95% CI 0.94 to 0.98) were similar. An older systematic review reported results consistent with the other two systematic reviews.⁵⁰ All of the systematic reviews included the large and longer-duration CLASS trial, which reported lower risks of withdrawal due to adverse events (18 percent vs. 21 percent) and withdrawal due to GI adverse events (8.7 percent vs. 11 percent) with celecoxib compared to diclofenac or ibuprofen.⁵⁴

A meta-analysis of 21 randomized trials from the Pfizer registry reported results that were generally consistent with the systematic reviews.¹⁷⁰ It found celecoxib associated with lower risk of GI adverse events (20 percent) compared to naproxen (32 percent), ibuprofen (31 percent), or diclofenac (24 percent), as well as lower likelihood of withdrawal due to GI adverse events (4.2% vs. 5.0% to 8.5%). However, this study was rated poor quality, in part because it did not assess study quality and because raw event rates were pooled across studies, resulting in loss of randomization.

One new randomized trial (n=925) found celecoxib and diclofenac associated with no difference in risk of withdrawal due to adverse events (27% vs. 31%, respectively, p=0.22) or withdrawal due to GI adverse events (15 percent vs. 14 percent).⁵² A pooled analysis from three similarly designed trials of patients in Asia (total n=880) found no difference between celecoxib and diclofenac in risk of withdrawal due to adverse events (3.4% vs. 6.1%, p>0.05).⁸²

Partially Selective NSAIDs

Two systematic reviews^{89, 92} of randomized trials included in the original CER and one new systematic review⁵⁸ evaluated the tolerability of meloxicam, etodolac, or nabumetone compared to nonselective NSAIDs. The new systematic review found meloxicam associated with decreased risk of any adverse event (RR 0.91, 95% CI 0.84 to 0.99), any GI adverse event (RR 0.31, 95% CI 0.24 to 0.39), and withdrawals due to GI adverse events (RR 0.61, 95% CI 0.54 to 0.69), though there was no difference in the risk of withdrawal for any adverse event (RR 0.92, 95% CI 0.66 to 1.3).⁵⁸ The median Jadad quality score for the trials included in the systematic review was three (maximum five), indicating moderate overall quality. A meta-analysis of meloxicam studies included in the original CER reported similar findings, with lower risks of any GI event (OR 0.64; 95% CI 0.59 to 0.69) and withdrawals due to GI events (OR 0.59; 95% CI 0.52 to 0.67) with meloxicam compared with nonselective NSAIDs.⁹²

The new systematic review also evaluated tolerability of etodolac.⁵⁸ It found etodolac associated with a lower risk of any adverse event (RR 0.83, 95% CI 0.70 to 0.99) compared to nonselective NSAIDs, but there was no difference in risk of GI adverse events (RR 0.77, 95% 0.55 to 1.1), withdrawal due to adverse events (RR 0.93, 95% CI 0.77 to 1.1), or withdrawal due to GI adverse events (RR 0.95, 95% CI 0.54 to 1.6). Only two of 29 trials of etodolac scored 5 out of 5 on the Jadad quality scale; 7 received only 2 points.

In a meta-analysis included in the original CER, the incidence of GI adverse events was slightly but statistically significantly lower with nabumetone compared to nonselective NSAIDs (25 % vs. 28%, p=.007), corresponding to about one fewer event for every 34 patients treated with nabumetone.⁸⁹

Nonselective NSAIDs

A Cochrane review included in the original CER evaluated the tolerability of different NSAIDs.⁵⁶ The only relatively consistent finding was that indomethacin was associated with higher rates of toxicity than other NSAIDs, but it was not clear if these differences were statistically significant.

Aspirin and Salsalate

Five randomized trials (all included in the original CER) evaluated the efficacy or safety of aspirin or salsalate compared with nonaspirin NSAIDs in patients with arthritis.^{80, 171–174} All were short-term (≤ 12 weeks) and involved a total of 471 patients; of the subjects enrolled, only 4 had osteoarthritis of the hip/knee for every 100 patients with rheumatoid arthritis. Aspirin was associated with higher incidence of overall adverse events than salsalate (70% vs. 40%, p<0.05)⁸⁰ and diclofenac (61% vs. 46%; p<0.05);¹⁷³ these led to higher rates of withdrawals due to adverse events for aspirin compared with diclofenac (23% vs. 6%; p<0.05). Salsalate was associated with a higher incidence of overall adverse events compared to other nonselective NSAIDs in two^{171, 174} of three trials, but the actual rates were not reported.

The overall safety profile of salsalate has also been evaluated in the rheumatoid arthritis population using the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) databases. These studies reported summary measures of drug toxicity based on tabulations of mean frequencies of overall adverse events per patient years, weighted by severity, and adjusted for differences in demographic factors. Numerically larger index scores indicate greater levels of toxicity. The summary index score takes into account symptoms from all body systems, laboratory abnormalities, and all-cause hospitalizations.^175–178 Symptoms were assessed every 6 months using patient self-report in response to open-ended questions. Hospitalizations and deaths were ascertained from discharge summaries and death certificates. Descriptions of study methods varied, but the ARAMIS studies were somewhat vague with regard to patient selection and ascertainment methods; adverse events were not clearly defined or prespecified; exposure duration and length of followup were unclear; and adjustments were made only for demographic factors such as age and gender. Because the results of these studies are more subject to recall bias and had other methodological shortcomings, the findings that aspirin, salsalate, and ibuprofen were the least toxic among the NSAIDs studied (Table 10) are less convincing than if they were reported in more rigorously designed observational studies.

Acetaminophen

Four systematic reviews included in the original CER evaluated the efficacy and safety of acetaminophen compared with NSAIDs (selective or nonselective) for osteoarthritis.^179–182 We identified no new systematic reviews. One new randomized trial compared acetaminophen versus naproxen for osteoarthritis.¹⁸³ One new observational study evaluated risk of acute myocardial infarction associated with various NSAIDs compared to acetaminophen.¹⁰⁸

The systematic reviews generally met all criteria for good-quality systematic reviews, except that three^180–182 did not provide sufficient detail about trials that were excluded. The overall conclusion from the reviews was that NSAIDs were modestly superior to acetaminophen for general or rest pain (Table 11). For pain on motion and overall assessment of clinical response, NSAIDs also appeared modestly superior, though the differences were not always statistically significant.^{180, 181} Only two reviews assessed functional disability; neither found clear differences.^{180, 181}

The risk of adverse events with acetaminophen versus NSAIDs was assessed in three systematic reviews (Table 12).^{179, 180, 182} In two reviews, there were no differences in withdrawal due to any adverse event.^{179, 180} Acetaminophen was associated with lower risk of GI adverse events compared with nonselective NSAIDs in two systematic reviews (though not compared with coxibs)^{180, 182} and lower risk of withdrawals due to GI adverse events in one systematic review.¹⁸⁰ One systematic review found no difference between NSAID and acetaminophen in serious GI, renal, or CV harms, but found few events in the primarily small, short-term trials (data not provided).¹⁸⁰

A new, fair-quality (high loss to followup) randomized trial found no differences in withdrawal due to lack of efficacy or WOMAC scores between acetaminophen 4 g once daily and naproxen 750 mg once daily for osteoarthritis after 6 months (n-=105) or 1 year (n=476).¹⁸³ Acetaminophen and naproxen were also associated with similar rates of withdrawal due to adverse events (25% vs. 22%, NS), serious adverse events (3.5 percent vs. 2.5 percent), any adverse event (72 percent vs. 74 percent), renal adverse events (three total), or hepatic enzyme increases (three in acetaminophen group vs. zero in the naproxen group). Naproxen was associated with an increased risk of constipation (9.9% vs. 3.1%, p<0.002) and peripheral edema (3.9% vs. 1.0%, p<0.033) compared to acetaminophen.

Clinical trials of acetaminophen have not been large enough to assess serious but less common complications such as PUBs, myocardial infarction, acute renal failure, or hypertension. Several observational studies included in the original CER provide some additional information about the safety of acetaminophen relative to NSAIDs. A fair-quality nested case-control study of 1,197 cases and 10,000 controls from a population-based cohort of 458,840 people in the General Practice Research Database found current acetaminophen use associated with a lower risk for symptomatic peptic ulcer (adjusted RR 1.9, 95% CI 1.5 to 2.3) than NSAID use (adjusted RR 4.0, 95% CI 3.2 to 5.1) when each was compared with nonuse.¹⁸⁴ There was no clear relationship between higher acetaminophen dose and increased risk for symptomatic ulcers. An earlier analysis on the same database also found current acetaminophen use associated with a lower risk for upper GI bleeds or perforations (adjusted RR 1.3, 95% CI 1.1 to 1.5) than current NSAID use (adjusted OR 3.9, 95% CI 3.4 to 4.6), each compared with nonuse.⁹⁸ A retrospective cohort study of elderly patients found that patients using lower doses of acetaminophen (<2,600 mg once daily) had lower rates of GI events (defined as GI-related hospitalizations, ulcers, and dyspepsia) compared with users of NSAIDs (RR 0.73, 95% CI 0.67 to 0.80 for 1,951 to 2,600 mg once daily), but the risks were similar at higher doses (RR 0.93 to 0.98).¹⁸⁵ Although GI hospitalization rates were not reported separately, the authors noted that dyspepsia was responsible for most of the increase in GI events in the high-dose acetaminophen groups. A meta-analysis on individual patient data from three earlier retrospective case-control studies (2472 cases) was consistent with the above studies.¹⁸⁶ It found acetaminophen associated with a minimal increase in the risk for serious upper GI bleeding (OR 1.2, 95% CI 1.1 to 1.5). By contrast, nonselective NSAIDs were associated with higher risks, though estimates of risk varied considerably for different NSAIDs (OR 1.7 for ibuprofen to 35 for ketoprofen).

No randomized trial evaluated the association between acetaminophen use and myocardial infarction or other thromboembolic CV events. An analysis from the large, prospective Nurses’ Health Study found heavy use of acetaminophen (more than 22 days/month) associated with an increased risk of CV events (RR 1.4, 95% CI 1.1 to 1.6) similar to that with heavy use of NSAIDs (RR 1.4, 95% CI 1.3 to 1.6).¹⁸⁷ Dose-and frequency-dependent effects were both significant. A new retrospective cohort study found no difference in risk of acute myocardial infarction between celecoxib, ibuprofen, diclofenac, or naproxen versus acetaminophen (Table 13, Appendix H).¹⁰⁸

The association between renal failure and acetaminophen use was evaluated in several case-control studies included in the original CER. Interpretation of these studies is difficult because many had important flaws (such as failure to identify patients early enough in the course of their disease to ensure that the disease had not led to a change in the use of analgesics, failure to specify diagnostic criteria, failure to adjust for the use of other analgesics, incompleteness of data on exposure, and use of proxy respondents) in the collection or analysis of data.¹⁸⁸ The largest (926 cases) case-control study was designed to try to avoid many of these flaws, though results remain susceptible to confounding by indication.¹⁸⁹ It found regular use of acetaminophen associated with an increased risk for chronic renal failure (Cr >3.8 for men and >3.2 for women) compared with nonuse (OR 2.5, 95% CI 1.7 to 3.6). Use of NSAIDs was not associated with an increased risk (OR 1.0). A prospective cohort study of 1,697 women in the Nurses’ Health Study found increased lifetime acetaminophen exposure associated with a higher risk of decline in glomerular filtration rate of 30% or greater (p<0.001), though NSAIDs were not (p=0.88).¹⁹⁰ The absolute risk of renal function decline, however, was modest, even in women reporting high amounts of lifetime acetaminophen use. Compared with women consuming less than 100 g of cumulative acetaminophen, the odds of a decline in GFR of at least 30 mL/min per 1.73 m² for women consuming more than 3,000 g was 2.04 (95% CI, 1.28 to 3.24). By contrast, analyses of men in the Physicians’ Health Study found no association between acetaminophen or NSAIDs and change in kidney function.^{191, 192}

The risk of heart failure associated with acetaminophen has not been well studied. In a single study using the General Practice Research Database, current use of acetaminophen was associated with a higher risk of newly diagnosed heart failure compared with nonuse (RR 1.3, 95% CI 1.1 to 1.7), though the risk was lower compared with current use of NSAIDs (RR 1.6, 95% CI 1.2 to 2.0).¹⁶³

The risk of hypertension has been evaluated using data from the Nurses’ Health Studies^193–195 and the Physicians’ Health Study.¹⁹⁶ In the Nurses’ Health Studies, acetaminophen and NSAIDs were associated with similar increases in risk of incident hypertension (Table 13). In the Physicians’ Health Study, there was no association between NSAID or acetaminophen use and hypertension.

Glucosamine and Chondroitin

Five new systematic reviews (Appendix I)^197–201 and four systematic reviews ^202–205 included in the original CER evaluated benefits and harms of glucosamine and chondroitin. New trials identified for this update include one trial of glucosamine versus acetaminophen and placebo,²⁰⁶ two trials of glucosamine versus placebo,^{207, 208} four trials of chondroitin versus placebo,^209–212 and one trial of the combination of glucosamine and chondroitin versus placebo (Table 14, Appendix I).²¹³ We also identified two followup analyses from the previously included Glucosamine/chondroitin Arthritis Intervention Trial (GAIT).^{214, 215}

Previous Bleeding Ulcer

Two randomized trials included in the original CER^{233, 234} and one new trial²³⁵ compared the risk of GI harms in patients with a recent bleeding ulcer randomized to celecoxib versus the combination of celecoxib plus a PPI (Table 16).

In two fair-quality, 24-week trials (total n=529) included in the original CER of patients with a history of a recent bleeding ulcer, rates of recurrent bleeding were similar for celecoxib (200 mg daily 3.7 percent and twice a day 4.9 percent) and the combinations of extended-release diclofenac 75 mg twice a day plus omeprazole 20 mg daily (6.3 percent)²³³ or naproxen 250 mg three times a day plus lansoprazole 30 mg a day (6.3 percent)²³⁴ (differences not statistically significant). There were also no differences between celecoxib and either combination therapy in GI, renal, and CV adverse events or in rates of withdrawal due to adverse events. One exception was that celecoxib 200 mg daily was associated with a higher rate of dyspepsia than naproxen 250 mg three times a day plus lansoprazole 30 mg daily in one trial.²³⁶

A new, fair-quality, 12-month trial (n=273) of patients with recently healed GI bleeding (following cessation of NSAID therapy and treatment with a PPI for 8 weeks) found celecoxib 200 mg twice daily plus esomeprazole 20 mg twice daily associated with significantly fewer ulcer bleeding recurrences compared with celecoxib alone.²³⁵ After a median of 13 months, zero events occurred in the combined treatment group, compared with 12 (8.9 percent) in the celecoxib alone group (p=0.0004). Similar results were found among those taking low-dose aspirin (0% vs. 19%; p=0.03). Other adverse events and rates of discontinuations were similar between groups.

Underlying Cardiovascular or Renal Risk

We found no randomized trials designed to assess whether the relative harms and benefits associated with different oral treatments for osteoarthritis vary according to underlying CV or renal risk. A new systematic review of long-term celecoxib trials found that risk of CV events doubled between patients at low and moderate baseline CV risk (HR 2.0, 95% CI 1.5 to 2.6) and doubled again in patients at high baseline risk (HR, high risk to low risk, 3.9, 95% CI 2.3 to 6.7).¹¹⁴ Most^{132, 133, 145, 237} but not all¹³⁴ large observational studies also found a history of coronary heart disease, coronary heart disease risk factors, or categorization as high CV risk associated with increased risk estimates with NSAIDs as a group. A good-quality, population-based study of a very high-risk group of 58,000 Danish patients with previous myocardial infarction found hazard ratios for death of 2.6 (95% CI 2.2 to 3.1) for celecoxib, 1.5 (95% CI 1.4 to 1.7) for ibuprofen, 2.4 (95% CI 2.1 to 2.8) for diclofenac, and 1.3 (95% CI 1.2 to 1.4) for other NSAIDs compared to nonuse of NSAIDs.²³⁸ Based on the rates of death in this population (95 per 1,000 person-years in those not using NSAIDs), the estimated number of patients needed to treat with an NSAID for one year to cause one additional death was 14 (95% CI 10 to 24) for celecoxib, 45 (95% CI 29 to 102) for ibuprofen, and 24 (95% CI 16 to 45) for diclofenac.

We found no trials evaluating comparative risks of different oral medications in patients with known congestive heart failure. A new cohort study found celecoxib, ibuprofen, diclofenac, and naproxen associated with similar risk of hospitalization due to acute myocardial infarction (HR estimates ranged from 1.3 to 1.5) or hospitalization due to congestive heart failure (HR estimates ranged from 1.2 to 1.4) following an index hospitalization for congestive heart failure, though celecoxib (HR 1.8, 95% CI 1.6 to 1.9) and diclofenac (HR 2.1, 95% C I 2.0 to 2.2) were associated with greater risk of death compared to ibuprofen (HR 1.3, 95% CI 1.2 to 1.4) or naproxen (HR 1.2, 95% CI 1.1 to 1.4).¹⁶² A new nested case-control study found indomethacin associated with increased risk of heart failure compared to celecoxib (OR 2.0, 95% CI 1.2 to 3.6) in patients older than 66 recently hospitalized for heart failure.¹⁵⁸ There was no difference in risk of heart failure between other nonselective NSAIDs (diclofenac [OR 0.82, 95% CI 0.51 to 1.3] and ibuprofen [OR 1.5, 0.66 to 3.2]) or acetaminophen (OR 1.2, 95% CI 0.92 to 1.4) relative to celecoxib. A retrospective cohort study included in the original CER based on the same Canadian database found nonselective NSAIDs associated with an increased risk of death (HR 1.5, 95% CI 1.2 to 2.0), recurrent heart failure (HR 1.2, 95% CI 0.92 to 1.6), or either (HR 1.3, 95% 1.0 to 1.6) in similarly high risk patients.¹⁶¹

One new trial (n=88) compared ibuprofen, acetaminophen, and piroxicam in hypertensive patients on lisinopril/hydrochlorothiazide or amlodipine.²³⁹ Both NSAIDs blunted the effects of the antihypertensive drugs, with the lisinopril/hydrochlorothiazide combination more affected. Acetaminophen had almost no effect on blood pressure.

Nonselective NSAIDs

Concomitant use of anticoagulants and nonselective NSAIDs increase the risk of GI bleeding three-to sixfold compared to anticoagulants alone.^{240, 241} Three observational studies included in the original CER evaluated risk of bleeding in patients on an NSAID plus anticoagulants versus an anticoagulant alone.^242–244 We identified no new studies.

A good-quality nested case-control study of elderly (>66 years old) patients on warfarin in Ontario, Canada, evaluated the association between hospitalization for upper GI bleeding (361 cases) and use of selective or nonselective NSAIDs.²⁴² It found that after adjustment for potential confounders (antiplatelet agents, hypoglycemic agents, glucocorticoids, gastroprotective agents, history of previous bleed, and comorbidities), recent use of nonselective NSAIDs (OR 1.9, 95% CI 1.4 to 3.7), and celecoxib (OR 1.7, 95% CI 1.2 to 3.6) were associated with increased and overlapping risks for upper GI bleeding, compared with nonuse. Because this study relied on pharmacy databases to identify exposures prior to hospitalization, it could not assess the confounding effects of over-the-counter use of aspirin, other NSAIDs, or acid suppressive medications. It also was unable to control for variations in INR level and the risk for bleeding.

In a fair-quality cohort study of patients enrolled in an anticoagulation clinic, 1,145 patients who were receiving warfarin (INR ≥1.4) but not aspirin, acetaminophen, or other nonselective NSAID were indentified retrospectively. ²⁴³ Eleven percent (n=123) were taking celecoxib concurrently with warfarin during the study period. The risk of major bleeding events (requiring hospitalization, transfusion or resulting death) was not significantly elevated in the celecoxib group (RR 1.0, 95% CI 0.14 to 7.8).

A smaller, fair-quality nested retrospective study of patients in the Netherlands evaluated the risk of bleeding in anticoagulated patients receiving partially selective (meloxicam or nabumetone) or nonselective NSAIDs.²⁴⁴ This study differed from the others in that it included all cases of bleeding, including minor visible bleeding, hematoma, or black tarry stools. Patients were identified as having exposure to anticoagulation by being enrolled in a pharmacy-based anticoagulation program. Bleeding events were identified through the pharmacy clinic records, and discharge diagnosis records (national database). Patient questionnaires were sent out to those identified as having a bleeding event, to assess exposure status and comorbidities. Patients were interviewed over the phone if answers were incomplete or unclear. The response rates were significantly higher in the cases (approximately 70 percent) compared with controls (approximately 31 percent). The study found that nonselective NSAIDs were associated with an increased risk of bleeding compared with partially selective NSAIDs after adjustment for duration of use and INR level (OR 3.1, 95% CI 1.2 to 8.0).

Aspirin and Anticoagulation

In the original CER, we found no studies evaluating risks and benefits of concomitant anticoagulants and aspirin in patients with arthritis. No new studies were identified for this update. Combination therapy has been studied in patients with indications for thromboembolic prophylaxis. However, the results of those studies are not directly applicable to patients with arthritis because of important differences in the populations (particularly with regard to CV risk), and because aspirin was used in lower, prophylactic doses (rather than anti-inflammatory and analgesic doses). One fair-quality meta-analysis (did not evaluate quality of included trials) found major bleeding risk increased with warfarin plus aspirin versus warfarin alone (at the same intensity) in patients with mechanical heart valves (three trials, RR 1.58, 95% CI 1.02 to 2.44).²⁴⁵ In patients with recent myocardial infarction or atrial fibrillation (one trial each), the increase in risk was not statistically significant (RR 3.07, 95% CI 0.33 to 28.38 and RR 2.13, 95% CI 0.20 to 23.03, respectively). In patients with mechanical heart valves, the increase in bleeding risk was offset by a reduction in thromboembolic events (RR 0.33, 95% CI 0.19 to 0.58), and there was no difference in all-cause mortality (RR 0.78, 95% CI 0.29 to 1.83). Other evidence on the risks and benefits of combination therapy has focused on comparing warfarin plus aspirin to aspirin alone. A good-quality meta-analysis of 10 trials found the combination of warfarin plus aspirin increased the risk of major bleeding compared with aspirin alone following myocardial infarction or the acute coronary syndrome (RR 2.5, 95% CI 1.7 to 3.7).²⁴⁶ However, the increase in bleeding risk was offset by lower risks for myocardial infarction, ischemic stroke, and revascularization. Mortality did not differ.

Other Analgesics

No study evaluated risk of bleeding in anticoagulated patients on acetaminophen compared with those on NSAIDs. A small, randomized controlled trial found acetaminophen associated with greater increases in INR levels compared with placebo.²⁴⁷ Several observational studies have also found an association between excess anticoagulation and use of acetaminophen.^{248, 249} However, changes in INR are not the only important factor for predicting increased risk of bleeding. NSAIDs, for example, also affect platelet function and disrupt the gastric mucosal lining. Studies evaluating actual bleeding complications are necessary to better assess the comparative risks from acetaminophen and other NSAIDs.

No studies evaluated risk of bleeding in anticoagulated patients on glucosamine, chondroitin, or topical agents.

Celecoxib Plus Aspirin Compared With Nonselective NSAID Plus Aspirin

Beneficial effects of COX-2 selective inhibition on GI complication rates could be attenuated or eliminated by the concomitant use of aspirin. The original CER included two large trials (CLASS⁵⁴ and SUCCESS-1⁵⁵) and a systematic review⁵¹ that reported rates of ulcer complications associated with celecoxib and nonselective in subgroups of patients also using aspirin. Two new observational studies also compared risks of serious GI harms with celecoxib and nonselective NSAIDs in aspirin users.^{250, 251}

In the 20 percent of patients in CLASS who took aspirin in addition to their study drug, there was no difference in rates of ulcer complications (2.0% vs. 2.1%, p=0.92) or ulcer complications plus symptomatic ulcers (4.7% vs. 6.0%, p=0.49) in patients randomized to celecoxib versus those randomized to diclofenac or ibuprofen.^{54, 252} There were also no differences when celecoxib was compared to diclofenac and ibuprofen separately. In SUCCESS-1, among the 7 percent of the study population on aspirin, only four ulcer complications occurred, resulting in imprecise estimates (OR 2.0, 95% CI 0.14 to 27).⁵⁵ The systematic review found that use of aspirin increased the rate of endoscopic ulcers by about 6 percent in patients randomized to celecoxib (4.2% without aspirin and 9.9% with aspirin) or those randomized to a nonselective NSAID (18% and 24%, respectively).⁵¹ Celecoxib (any dose) was associated with a lower risk of endoscopic ulcers in aspirin users (RR 0.48, 95% CI 0.28 to 0.83), but ulcer complications were not reported in this subgroup.

The two new, fair-quality retrospective cohort studies were conducted by the same authors and evaluated the same Quebec health services administrative databases (Appendix H).^{250, 251} One study found use of celecoxib plus aspirin associated with a lower risk of hospitalizations due to ulcer complications compared with use of a nonselective NSAID plus aspirin (HR 0.62, 95% CI 0.48 to 0.80) among patients 65 years or older.²⁵⁰ The second study found that in patients 50 years and older, users of celecoxib plus aspirin had a lower risk of hospitalization for GI complications (HR 1.8, 95% CI 1.5 to 2.1) than users of diclofenac plus aspirin (HR 2.8, 95% CI 2.2 to 2.8, 95% CI 2.2 to 3.5), though estimates for ibuprofen plus aspirin (HR 1.4, 95% CI 0.8 to 2.7), naproxen plus aspirin (HR 2.2, 95% CI 1.6 to 3.0), and piroxicam plus aspirin (HR 2.0, 95% CI 0.8 to 5.4) were similar (each compared with users of acetaminophen without aspirin).²⁵¹

Impact of Concomitant PPI use on GI Risk With a Celecoxib or Nonselective NSAID

Subgroup analyses from four randomized controlled trials (reported in three publications) provided evidence on the effects of adding a PPI to celecoxib or nonselective NSAIDs in aspirin users.^{235, 253, 254} Only one fair-quality trial reported ulcer complications. ²³⁵ In patients (n=273) at very high risk for rebleeding (recently healed GI bleed) enrolled in this study, low-dose aspirin was started during the trial period in 43 patients. The rate of recurrent bleeding in this subgroup was 0 percent with celecoxib 200 mg twice daily plus esomeprazole 20 mg twice daily group compared with 19 percent in the group taking celecoxib alone (p=0.03).²³⁵

In two similarly designed, fair-quality trials (reported in one publication, total n=861) the pooled rate of endoscopically proven gastric ulcer in the subgroup also taking low-dose aspirin (n= 201) was significantly lower with naproxen plus a PPI (3 percent) compared with enteric coated naproxen alone (28%; p<0.001).²⁵³ A large, fair-quality trial of celecoxib versus naproxen plus lansoprazole in low-dose aspirin users (n = 1,045) found no difference in risk of endoscopically proven gastric or duodenal ulcers (9.9% vs. 8.9%, p=0.65).²⁵⁴ Post-hoc analyses showed no effect based on aspirin dose (81 mg or 325 mg daily).

Celecoxib

The original CER included a systematic review, a randomized trial not included in the systematic review, and two large observational studies on effects of aspirin on CV harms associated with celecoxib use. We identified no new studies.

A systematic review of 84 placebo-controlled trials of celecoxib that permitted aspirin use found a very similar risk of vascular events among aspirin users (RR 1.6, 95% CI 0.90 to 2.7) and aspirin nonusers (RR 1.5, 95% CI 1.1 to 2.0), though the absolute rate of events was higher in aspirin users (1.9 percent/year vs. 1.1 percent/year), perhaps due to higher baseline risk.¹²¹ In a large celecoxib polyp prevention trial not included in the systematic review, use or nonuse of low-dose aspirin did not affect the observed increased risk of thrombotic events.²⁵⁵ Consistent with these findings, two large observational studies found no significant interaction between concurrent NSAID and aspirin use and risk of myocardial infarction.^{134, 136}

Nonselective NSAIDs

It has been suggested that some nonselective NSAIDs may reduce or eliminate the CV benefits associated with low-dose aspirin.³⁶ In particular, ibuprofen is thought to be associated with unique pharmacokinetic and pharmacologic properties that could interfere with aspirin. Six observational studies^{108, 133, 256–259} and one subgroup analysis from a randomized trial²⁶⁰ evaluated effects of concomitant NSAIDs on CV risk in aspirin users (Table 17, Appendix H). The studies used heterogeneous designs, outcome measures, and methods of analysis, making it difficult to reach firm conclusions about comparative risks.

Three observational studies found no increase in risk of mortality²⁵⁷ or myocardial infarction^{133, 256} in users of a nonselective NSAID plus aspirin versus aspirin alone (Table 17). A subgroup analysis from a randomized trial also found no increased risk with short-term (<60 days) use of a nonselective NSAID plus aspirin compared to aspirin alone.²⁶⁰ The estimate for longer term use suggested increased risk, but was imprecise and not statistically significant.

For the effect of adding ibuprofen to aspirin, one fair-quality study of patients recently discharged from the hospital for a CV disease diagnosis found an increased risk of overall and CV mortality with the combination of ibuprofen and aspirin compared to aspirin alone (Table 17).²⁵⁸ The study did not report baseline characteristics of patients, although the analysis did control for potential confounders.

Two other observational studies evaluated risk of acute MI with ibuprofen plus aspirin versus aspirin alone.^{256, 259} A fair-quality case-control study found the risk of first nonfatal MI was elevated in those using ibuprofen plus aspirin compared with those using only aspirin, while a retrospective cohort study (also fair quality) found that adding ibuprofen to aspirin resulted in decreased risk of myocardial infarction (Table 17).^{256, 259} These studies used different methods, which could account for their discrepant findings. The case-control study identified controls from the community, used telephone interviews to collect exposure and covariate data, and considered the patient to be exposed to ibuprofen or aspirin if they reported using the drug(s) in the week prior to the event.²⁵⁶ Recall bias is a major concern with this study, and differences between groups suggest potentially important differences in baseline risk. The cohort study used Veterans Affairs prescription and medical records to identify regular users of ibuprofen and aspirin or aspirin alone with matching based on age, race, sex, and cholesterol levels.²⁵⁹ The study did not measure potential confounders or conduct adjusted analyses, and very limited information was provided about the patients’ comparability at baseline.

Two other observational studies found no statistically significant differences in risk between ibuprofen plus aspirin versus ibuprofen alone¹⁰⁸ or use of ibuprofen plus aspirin versus nonuse of NSAIDs (including aspirin),¹³³ but were not designed to assess risk associated with addition of ibuprofen to aspirin.