Table 1.
Overview of recent key clinical trials of COX2 inhibitors vs nonselective NSAIDs
| PRECISION28 | MEDAL51 | CONCERN29 | |
|---|---|---|---|
| Investigational agent | Celecoxib 100 mg BID (n=8,072) | Etoricoxib 90 mg once daily (n=11,787) | Celecoxib 100 mg BID (n=257) |
| Comparator | Naproxen 375 mg BID (n=7,969) or ibuprofen 600 mg TID (n=8,040) | Diclofenac 75 mg BID (n=11,717) | Naproxen 500 mg BID (n=257) |
| Design | Randomized, double-blind, parallel | Randomized, double-blind, parallel | Randomized, double-blind, parallel |
| Key inclusion criteria | Age ≥18 years RA or OA requiring daily NSAIDs High CV risk/established CV disease |
Age ≥50 years RA or OA requiring chronic NSAIDs |
Arthritis pain not relieved by basic analgesics Previous upper-GI bleeding during NSAID use Requirement for low-dose aspirin, or multiple CV risk factors |
| Aspirin use | Allowed (46% of patients) | Recommended | Recommended for all patients (used by 72%) |
| PPI use | Esomeprazole 20–40 mg once daily | Recommended | Esomeprazole 20 mg once daily |
| Primary end point | First occurrence of APTC event composite (noninferiority) | Thrombotic CV-event composite (noninferiority) | Recurrent GI bleeding within 6 months |
| Duration of therapy | Mean 20.3±16.0 months | Mean 19.4–20.8 months | Median 18 months |
| CV events | Primary-outcome event rates: 2.3%, 2.5%, and 2.7% for celecoxib, naproxen, and ibuprofen, respectively. HR (95% CI) 0.93 (0.76–1.12) for celecoxib vs naproxen, 0.85 (0.70–1.04) for celecoxib vs ibuprofen, and 1.08 (0.90–1.31) for ibuprofen vs naproxen (noninferiority P-values <0.001, <0.001, and<0.02, respectively) Results were consistent across subgroups based on low-dose aspirin use, indication for treatment, and in patients with or without existing CV disease |
The HR for thrombotic events with etoricoxib vs diclofenac was 0.96 (95% CI 0.81–1.15). The upper bound of the 95% CI was well below the prespecified noninferiority bound of 1.30 Results for the subgroup of patients on low-dose aspirin were consistent with those for the overall population (HR 0.89, 95% CI 0.69–1.14) for etoricoxib vs diclofenac, although there was a slightly greater numerical risk reduction for etoricoxib vs diclofenac in the subgroup of patients on low-dose aspirin compared with the overall study population |
The cumulative rate of serious CV events at 6 months was 4.4% (85% CI 2.4%–7.7%) in the celecoxib group and 5.5% (95% CI 3.3%–9.2%) in the naproxen group (P=0.543; crude HR 0.78, 95% CI 0.36–1.73; P=0.544) |
| GI events | CSGIE event rates were 0.5%, 0.7%, and 0.9% in the celecoxib, naproxen and ibuprofen groups, respectively HR (95% CI) for CSGIE end point 0.97 (0.67–1.40, P=0.86) for celecoxib vs naproxen and 0.76 (0.53–1.08, P=0.12) for celecoxib vs ibuprofen Composite CSGIE and iron- deficiency anemia of GI origin event rates were 1.1%, 1.5%, and 1.6% in the celecoxib, naproxen, and ibuprofen groups, respectively; HR for composite GI adverse-event end point 0.71 for celecoxib vs naproxen (P=0.01) and 0.65 for celecoxib vs ibuprofen (P=0.002) |
Discontinuations due to GI adverse events were significantly less frequent with etoricoxib than diclofenac Rates of lower-GI clinical events were similar for the two drugs: 0.32 (95% CI 0.25–0.39) per 100 patient- years for etoricoxib and 0.38 (95% CI 0.31–0.46) per 100 patient-years for diclofenac (HR 0.84, 95% CI 0.63–1.13) | Cumulative incidence of recurrent bleeding was 5.6% (95% CI 3.3%–9.2%) in the celecoxib group and 12.3% (8.8%–17.1%) in the naproxen group (P=0.008; crude HR 0.44, 95% CI 0.23–0.82; P=0.010) |
Abbreviations: APTC, Antiplatelet Trialists’ Collaboration; BID, bis in die (twice daily); CSGIE, clinically significant GI event; CV, cardiovascular; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; PPI, proton-pump inhibitor; RA, rheumatoid arthritis; TID, ter in die (thrice daily).