Evidence Table 3.3. Harms due to COX-2 inhibitors—Systematic reviews

Author, yearNReview characteristics/ qualityEligibility criteriaIntervention(s) (dose range)Results
Hooper, 2004 60 74,666 Included studies Inclusion
  • COX-2 vs. NSAID, misoprostol, PPI and H2
  • GI, CV, renal, other harms
  • RCTs
COX 2- selective (etodolac, meloxicam, nabumetone, nimesulide) vs. NSAIDs All-cause mortality:
RCTs: n = 68 Exclusion
  • Non-RCTs
  • No treatment
  • Children
  • < 21 d study period
COX-2 specific (celecoxib, rofecoxib) vs. NSAIDs Cox-2 selective (51 RCTs):
e-databases RR: 0.68 (0.3, 1.6), NS
n = 3 Cox-2 specific (17 RCTs):
Range years RR: 1.02 (0.6, 1.9), NS
1966 - 2002 Withdrawals due to harms:
Quality of SR Cox-2 selective (51 RCTs):
GoodRR: 0.93 (0.9, 1.0), NS
Cox-2 specific (17 RCTs):
RR: 0.82 (0.7, 0.9)^
Endoscopic GI ulcers:
Cox-2 selective (51 RCTs):
RR: 0.41 (0.2, 1.1), NS
Cox-2 specific (17 RCTs):
RR: 0.25 (0.2, 0.3), S
Symptomatic ulcers:
Cox-2 selective (51 RCTs):
RR: 0.41 (0.3, 0.7), S
Cox-2 specific (17 RCTs):
RR: 0.49 (0.38, 0.62), S
POB:
Cox-2 selective (51 RCTs):
RR: 0.61 (0.34, 1.10), NS
Cox-2 specific (17 RCTs):
RR: 0.55 (0.38, 0.80), S
GI symptoms:
Cox-2 selective (51 RCTs):
RR: 0.73 (0.7, 0.8), S
Cox-2 specific (17 RCTs):
RR: 0.81 (0.7, 0.9), S
Garner, 2002 61 4,465 Included studies Inclusion
  • RA pts (some with OA)
  • RCTs
  • Published
  • celecoxib vs. pb
  • celecoxib vs. other NSAID
Celecoxib vs. pb Celecoxib vs. pb :All-cause mortality: (3 RCTs) None
  • Withdrawals due to harms: (1 RCT)
    Cel 40mg (4%) vs. 200 mg (5%) vs. 400 mg (5%) vs. pb (6%), NS
  • Edema: (2 RCTs)
    Cel 1–2% vs. pb 0%
  • Endoscopic ulcers: NS
RCTs: n = 5 Exclusion
  • <50 pts in each arm
  • <1mo treatment
Celecoxib vs. NSAIDs Celecoxib vs. NSAIDs:
  • Arterial hypertension: (1 RCT) Cel 4/236 (1%) vs. diclofenac 5/329 (2%)
  • Edema: (3 RCTs)
    Cel (400–800 mg/d) & naproxen 2%
    Cel 11/236 (3%) vs. diclofenac 5/329 (2%)
  • Endoscopic ulcers: (2 RCTs)
    RR: 0.22 (0.15–0.32), S
    Used FDA CLASS study description
  • Endoscopic ulcers: (52 wks)
    Celecoxib (22/3105) was S lower than for the NSAID's pooled (39/ 3,124; p=0.02) & for ibuprofen alone (29/ 1,573; p=0.001) but not for diclofenac alone (29/1,573)
e-databases Used FDA CLASS study description
n = 3
Range years
1966 - 2002
Quality of SR
Good
Deeks, 2002 62 15,187 Included studies Inclusion
  • OA/ RA
Celecoxib vs. pb Celecoxib vs. pb
  • Withdrawals due to harms: (5 RCTs)
    RR: 1.49 (1.15, 1.92), S
  • Endoscopic GI ulcers: RR: 1.53 (0.73, 3.21), NS
RCTs: n = 9 Exclusion
  • NR
Celecoxib vs. NSAIDs
  • Celecoxib vs. NSAIDs
  • Withdrawals due to harms: (8 RCTs)
    RR: 0.86 (0.72, 1.04), NS
  • Endoscopic GI ulcers: (vs. naproxen, diclofenac): RR: 0.25 (0.12, 0.53)
  • POB: (vs. ibuprofen, diclofenac)
    RR: 0.55 (0.26, 1.14), NS
  • PUB: (vs. ibuprofen, diclofenac)
    RR: 0.61 (0.39, 0.96), S
e-databases
n = 3
Range years
1998 - 2001
Quality of SR
Fair
Edwards, 2004 63 5,726 Included studies Inclusion
  • Pts: OA or RA
  • Double-blind RCTs
  • Valdecoxib vs. pb or NSAIDs
Valdecoxib 10 –20 mg/d vs. pb Valdecoxib vs. pb:
  • Withdrawals due to harms: RR: 0.9 (0.7, 1.3), NS
  • Significant renal events: RR: 2.9 (1.4, 5.7), S
  • Endoscopic GI ulcers: RR: 0.9 (0.5, 1.6), NS
RCTs: n = 9 Exclusion
  • NR
Valdecoxib 10 –20 mg/d vs. NSAIDs (ibuprofen, diclofenac, naproxen) Valdecoxib vs. NSAIDs: (9 RCTs)
  • Withdrawals due to harms: RR: 0.6 (0.5, 0.7), S
  • Acute MI: Valdecoxib 3/2,733 (0.1%) vs. NSAID 11/1,846 (0.6%), S
  • Edema: 2% each group, NS
  • Significant renal events: RR: 0.7 (0.5, 1.0), NS
  • Endoscopic GI ulcers: RR: 0.4 (0.3, 0.5), S
  • POB: RR: 0.4 (0.2, 1.2), NS
e-databases
NR
Range years
2002 - 2003
Quality of SR
Good
Garner, 2005 64 NR Included studies Inclusion
  • Pts with OA any age or sex
  • Published RCTs
  • Rofecoxib vs. pb or active comparators
  • Efficacy & safety outcomes
Rofecoxib vs. pb Rofecoxib vs. pb:
  • Withdrawals due to harms: (6 RCTs)
    12.5 mg/d: RR: 2.18 (1.34–3.55), S
    25 mg/d: RR: 1.56 (0.94, 2.59)
    50 mg/d: RR: 2.04 (1.24, 3.36), S
  • All symptoms and endoscopic ulcers: NS
  • Total adverse events: RR: 1.32 (1.11, 1.56) @ 6 wks; longer durations, NS
RCTs: n = 26 Exclusion
  • Unpublished RCTs
Rofecoxib vs. NSAIDs (diclofenac, naproxen, ibuprofen, nimesulide, nabumetone, paracetamol, celecoxib) Rofecoxib vs. diclofenac (150 mg/d):
  • Withdrawals due to harms: (2 RCTs)
    12.5 mg/d: RR: 0.71 (0.52–0.97)
    25 mg/d: RR: 0.70 (0.51–0.95)
  • PUB: RR: 0.25 (0.03, 2.25), NS
e-databases Rofecoxib vs. naproxen: (1 RCT)
  • Acute MI: RR: 4.98 (0.58, 42.57), NS
  • Acute stroke: RR: 0.08 (0.00, 1.36), NS
  • Arterial hypertension: RR: 1.22 (0.89, 1.68), NS
  • PUB: RR: 0.14 (0.01, 2.77), NS
n = 3 Rofecoxib vs. nabumetone: (3 RCTs)
  • Arterial hypertension: RR: 1.46 (0.53, 4.12), NS
  • Edema: RR: 1.41 (0.72, 2.77), NS
Range years Rofecoxib vs. ibuprofen:
  • Endoscopic GI ulcers: RR: 0.28 (0.19, 0.42), S
  • PUB: RR: 0.25 (0.03, 2.26), NS
1966 - 2004 Rofecoxib (25 mg) vs. celecoxib (200 mg):
  • Withdrawals due to harms: (9 RCTs)
    RR: 1.03 (0.77, 1.39), NS
  • Arterial hypertension: (2 RCTs)
    RR: 3.51 (0.73, 16.84), NS
  • Edema: RR: 1.39 (0.63, 3.08), NS
Quality of SR
Good
Garner, 2005 65 NR Included studies Inclusion
  • Pts with RA any age or sex
  • RCTs
  • Rofecoxib vs. pb or active comparators
  • Efficacy & safety outcomes
Rofecoxib (12.5–50 mg/d) vs. pb Rofecoxib vs. pb:
  • Withdrawals due to harms:
    Rofe 5 mg (3%) vs. 25 mg (3.2%) vs. 50 mg (4.7%) vs. pb (6.2%), NS
  • GI outcomes: NS
  • Edema & hypertension: NS between 3 doses of rofecoxib & pb.
RCTs: n = 2 Exclusion
  • < 50 pts included in RCT
  • Duration treatment < 4 wks
  • Used concomitant intra-articular corticosteroid therapy
Rofecoxib (12.5–50 mg/d) vs. naproxen (1 g/d) Rofecoxib vs. naproxen (VIGOR):
  • All-cause mortality: 0.5% vs. 0.4%, NS
  • CV-mortality: both 0.2%, NS
  • Withdrawals due to harms: (1 RCT)
    RR: 1.02 (0.92, 1.12), NS
  • Acute MI: (1 RCT)
    RR: 5.0 (1.5, 13.2), S
  • All-acute stroke: (1 RCT)
    RR: 1.37 (0.55, 3.41), NS
  • Ischemic stroke: RR: 1.12 (0.43, 2.91), NS
  • TIA: RR: 4.98 (0.24, 103.77), NS
  • POB: RR: 0.43 (0.24, 0.77), S
e-databases
n = 5
Range years
1966 - 2000
Quality of SR
Good
Gomez Cerezo, 2003 66 45,761 Included Studies Inclusion
  • Cox 2 specific
  • RCTs
Rofecoxib (12.5–50 mg/d) or celecoxib (50–800 mg/d) vs. NSAIDs (naproxen 1g/d, ibuprofen 2.4 g/d, diclofenac 100–150 mg/d) or pb Rofecoxib vs. naproxen
  • HTN (withdrawals): (1 RCT) RR: 4.67 (1.93, 11.28), S
  • CHF: (1 RCT): RR: 2.11 (0.96, 4.67), NS
  • Edema (withdrawals): (1 RCT)
    RR: 1.92 (0.98, 3.75), NS
  • PUB: RR: 0.46 (0.34, 0.63), S
  • POB: RR: 0.43 (0.24, 0.77), S
    rofecoxib vs. Ibuprofen & diclofenac:
  • PUB: RR: 0.51 (0.26, 1), NS
RCTs: n = 3 Exclusion
  • non-English
Celecoxib vs. NSAID
  • POB: RR: 0.10 (0.01, 0.81), S
    celecoxib vs. Ibuprofen & diclofenac:
  • POB: RR: 0.60 (0.25, 1.40), NS
  • PUB: RR: 0.61 (0.39, 0.96), S
e-databases
n = 1
Range years
1998 - 2002
Quality of SR
Poor
Mukherjee, 2001 67 18,064 Included studies Inclusion
  • Pts without previous CV event
  • COX-2 (rofecoxib, celecoxib)
  • Double-blind RCT
Rofecoxib (50 mg/d) vs. naproxen (1 g/d) Rofecoxib vs. naproxen: (1 RCT)
  • Serious CV events:
    Low CV risk: RR: 1.89 (1.03, 3.45), S
    High risk (ASA indicated): RR: 4.89 (1.41, 16.88), S
RCTs: n = 4 Exclusion
  • Non-RCTs, RCTs reporting non-CV adverse events
e-databases
n = 1
Range years
1998 - 2001
Quality of SR
Fair
Juni, 2004 68 25,273 Included studies Inclusion
  • RCTs & observational studies
  • Rofecoxib vs. NSAID or pb
  • Pts with chronic musculoskeletal disorders
  • Fatal or nonfatal MI, stroke, CV mortality, serious CV events
Rofecoxib vs. pb or NSAIDs Rofecoxib vs. NSAIDS : (9–17 RCTs)
  • Acute MI: RR: 2.24 (1.24, 4.02), S
  • Stroke/TIA: RR: 1.02 (0.54, 1.93), NS
  • Death due to CV harms:
    RR: 0.79 (0.29, 2.19), NS
  • Serious CV events: RR: 1.55 (1.05, 2.29), S
RCTs: n = 18 Exclusion
  • NR
Rofecoxib vs. pb:
  • Acute MI: RR: 1.04 (0.34, 3.12), NS
Case-control: n = 8 Rofecoxib vs. no naproxen NSAID:
  • Acute MI: RR: 1.55 (0.55, 4.36), NS
e-databases Rofecoxib vs. naproxen:
  • Acute MI: RR: 2.93 (1.36, 6.33), S
    12.5 mg/d RR: 2.71 (0.99, 7.44), NS
    25 mg/d RR: 1.37 (0.52, 3.61), NS
    50 mg/d RR: 2.83 (1.24, 6.43), S
n = 4
Range years
1966 - 2004
Quality of SR
Good
Rostom, 2003 59 86,702 Included studies Inclusion
  • OA pts, RA > 18 y, chronic use (> 4 wks) NSAID
Celecoxib vs. NSAID (naproxen, diclofenac, ibuprofen) Celecoxib vs. NSAID:
  • Endoscopic ulcers: RR: 0.28 (0.23, 0.35), S
RCTs: n = 37 Exclusion
  • NR
Rofecoxib vs. NSAID Celecoxib vs. diclofenac:
  • Endoscopic ulcers: RR: 0.45 (0.15, 1.29), NS
e-databases All Cox-2 vs. NSAID Rofecoxib vs. NSAIDs:
  • Endoscopic ulcers: RR: 0.25 (0.20, 0.32), S
n = 8 Meloxicam vs. NSAIDs:
  • POB: RR: 0.50 (0.22 –1.17), NS
Range years All Cox 2 vs. NSAIDs:
  • POB: RR: 0.45 (0.32, 0.63), S
  • Endoscopic ulcers: RR: 0.27 (0.23, 0.32), S
1966 - 2002
Quality of SR
Good
Ashcroft, 2001 69 4,632 Included studies Inclusion
  • Pts with RA & OA who had scheduled endoscopies
  • Celecoxib
  • RCTs
Celecoxib vs. NSAIDs (ibuprofen, diclofenac, naproxen) or pb
  • Endoscopic ulcers:
RCTs: n = 5 Exclusion
  • Healthy population not undergone by endoscopy
Celecoxib vs. naproxen:
e-databases 200 mg/d: RR: 0.22 (0.13, 0.37), S
n = 3400 mg/d: RR: 0.24 (0.17, 0.33), S
Range years Celecoxib vs. diclofenac:
1988 - 200012 wks: RR: 0.73 (0.45, 1.2), NS
Quality of SR 24 wks: RR: 0.24 (0.11, 0.52), S
Fair Celecoxib vs. Ibuprofen:
RR: 0.30 (0.20, 0.46), S
Celecoxib vs pb:
200 mg/d: RR:1.96 (0.85, 4.55)
400 mg/d: RR:2.35 (1.02, 5.38)
Goldstein, 2004 70 10,305 Included studies Inclusion
  • Pts with RA and/or OA
  • RCTs (long-term, open-label)
Valdecoxib vs. pb or NSAIDs Valdecoxib vs. pb:
  • PUB: RR :3.8 (0.22–65.70), NS
RCT: n=8 Exclusion
  • NR
Valdecoxib vs. NSAIDs:
  • POB (8 RCTs): (Valdecoxib 0.69%; NSAIDs 1.96%) RR: 0.14 (0.04–0.51), S
    Non - ASA users: (Valdecoxib 0.29%; NSAIDs 2.08%): RR: 0.35 (0.14–0.87), S
Cohorts: n = 3 Valdecoxib + ASA = 9-fold increase risk of bleeding
e-databases NSAIDS + ASA = did not increase risk further
NR Open-label: dose-reponse not seen with valdecoxib
Range years
NR
Quality of SR
Fair
Schoenfeld, 1999 71 20,374 Included studies Inclusion
  • Adult pts
  • Meloxicam vs. other non-COX 2 NSAID
  • GI events: dyspepsia, nausea/vomiting, abdominal pain, diarrhea, perforations, ulcers, bleeds, & withdrawals due to GI events
  • RCTs (including crossover with washout period)
Meloxicam (7.5 to 15 mg) vs. NSAID
  • Overall GI harms: OR: 0.64 (0.59, 0.69), S
  • PUB: OR: 0.52 (0.28, 0.96), S
  • Dyspepsia: OR: 0.73 (0.64, 0.84), S
  • Withdrawals due to GI harms:
    OR: 0.59 (0.52, 0.67), S
RCTs: n = 10 Exclusion
  • NR
e-databases
n = 1
Range years
1990 - 1998
Quality of SR
Fair
Eisen, 2005 72 4,394 Included studies Inclusion
  • Adult pts ≥ 18 y withOA or RA
  • Phase III RCTs
  • Valdecoxib use
Valdecoxib (10–20 mg/d) vs. pb or other NSAIDs (ibuprofen, diclofenac, naproxen)
  • Dyspepsia:
    Valdecoxib vs. NSAIDs: HR =1.0
    Valdecoxib vs. pb:
    Valdecoxib: HR = 0.56 (0.45–0.69)
    Pb: HR= 0.59 (0.45–0.79)
RCTs: n = 5 Exclusion
  • Pts with concomitant GI, renal, hepatic or coagulation disorder or malignancy
e-databases
NR
Range years
NR
Quality of SR
Fair

N = number of participants; y = year(s); mo = month(s); wk = week(s); d = day(s); n = number; pts = patients; hx = history; NR = not reported; vs. = versus; pb = placebo; ASA = acetylsalicylic acid/aspirin; RCT(s) = randomized control trial(s); NSAID = non steroid anti-inflammatory drug; RR = relative risk; OR = odds ratio; NS = nonstatistically significant difference; S = statistically significant difference; ⁁ high heterogeneity; GI = gastrointestinal; SR = systematic review; Cox-2 = Cox-2 inhibitors; PPI = proton pump inhibitors; H2 = H2 blockers; CV = cardiovascular; OA = osteoarthritis; RA = rheumatoid arthritis; FDA = food and drug administration; Cel = celecoxib; POB = perforation obstruction, bleed; PUB = perforation ulcer bleed; CHF = congestive heart failure; TIA = transitory ischemic attack; HTN = arterial hypertension

From: Appendix 8. Figures and Tables

Cover of Use of Aspirin and NSAIDs to Prevent Colorectal Cancer
Use of Aspirin and NSAIDs to Prevent Colorectal Cancer [Internet].
Evidence Syntheses, No. 45.
Rostom A, Dube C, Lewin G.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.