Table 4.

Incidence of Adverse Events after Randomization According to Celecoxib Dose, Stratified by CYP2C9 Genotype^a

	Placebo	Celecoxib, 200 mg Twice Daily	Celecoxib, 400 mg Twice Daily
Cardiovascular disordersb
All patients
No. with event/No. at risk	24/557	34/547	41/549
Cumulative incidence, 3 yrs, % ± SE	5.1 ± 1.1	7.4 ± 1.3	9.0 ± 1.4
RR (95% CI)	1.0	1.41 (0.83–2.37)	1.69 (1.02–2.80)
By genotype
Patients with wild-type genotypes
No. with event/No. at risk	18/377	29/358	25/362
Cumulative incidence, 3 yrs, % ± SE	5.7 ± 1.4	9.6 ± 1.8	8.1 ± 1.6
RR (95% CI)	1.0	1.62 (0.90–2.92)	1.37 (0.75–2.51)
Patients with CYP2C9*2 genotypes
No. with event/No. at risk	4/121	3/116	8/118
Cumulative incidence, 3 yrs, % ±	3.9 ±1.9	2.8 ± 1.6	9.4 ± 3.2
RR (95% CI)	1.0	0.81 (0.18–3.63)	2.75 (0.82–9.25)
Patients with CYP2C9*3 genotypes
No. with event/No. at risk	2/59	2/73	8/69
Cumulative incidence, 3 yrs, % ± SE	4.4 ±3.0	3.4 ± 2.4	13.3 ± 4.4
RR (95% CI)	1.0	0.80 (0.11–5.67)	2.69 (0.56–12.79)
Renal and hypertensive disordersc
All patients
No. with event/No. at risk	97/557	126/547	99/549
Cumulative incidence, 3 yrs, % ± SE	19.8 ± 1.9	26.2 ± 2.1	20.8 ± 2.0
RR (95% CI)	1.0	1.37 (1.05–1.79)	1.02 (0.77–1.35)
By genotype
Patients with wild-type genotypes
No. with event/No. at risk	66/377	76/358	63/362
Cumulative incidence, 3 yrs, % ± SE	20.3 ± 2.3	23.6 ± 2.5	20.5 ± 2.4
RR (95% CI)	1.0	1.23 (0.88–1.71)	0.99 (0.70–1.40)
Patients with CYP2C9*2 genotypes
No. with event/No. at risk	22/121	25/116	20/118
Cumulative incidence, 3 yrs, % ±SE	19.2 ± 3.9	25.0 ± 4.5	19.9 ± 4.2
RR (95% CI)	1.0	1.27 (0.71–2.25)	1.00 (0.55–1.85)
Patients with CYP2C9*3 genotypes
No. with event/No. at risk	9/59	25/73	16/69
Cumulative incidence, 3 yrs, % ± SE	17.2 ± 5.6	41.0 ± 6.5	23.4 ± 5.5
RR (95% CI)	1.0	2.64 (1.22–5.68)	1.30 (0.57–2.97)
Gastrointestinal ulceration/hemorrhaged
All patients
No. with event/No. at risk	57/557	56/547	55/549
Cumulative incidence, 3 yrs, % ± SE	11.9 ± 1.6	11.8 ± 1.6	11.7 ± 1.5
RR (95% CI)	1.0	0.97 (0.67–1.41)	0.95 (0.66–1.38)
By genotype
Patients with wild-type genotypes
No. with event/No. at risk	41/377	35/358	38/362
Cumulative incidence, 3 yrs, % ± SE	12.9 ± 2.0	10.9 ± 1.8	12.2 ± 1.9
RR (95% CI)	1.0	0.84 (0.54–1.32)	0.92 (0.59–1.43)
Patients with CYP2C9*2 genotypes
No. with event/No. at risk	10/121	16/116	9/118
Cumulative incidence, 3 yrs, % ± SE	8.5 ± 2.7	17.2 ± 4.1	9.5 ± 3.1
RR (95% CI)	1.0	1.85 (0.84, 4.07)	0.99 (0.40, 2.46)
Patients with CYP2C9*3 genotypes
No. with event/No. at risk	6/59	5/73	8/69
Cumulative incidence, 3 yrs, % ± SE	13.7 ±5.3	7.9 ± 3.4	12.1 ± 4.3
RR (95% CI)	1.0	0.62 (0.19–2.02)	0.98 (0.34–2.84)

^aWild-type genotypes include individuals with no *2 (R144C) or *3 (I359L) alleles. CYP2C9*2 genotypes include individuals with ≥ one *2 allele. CYP2C9*3 genotypes include individuals with ≥ one *3 allele. Individuals with one *2 allele and one *3 allele were classified as having CYP2C9*3 genotypes. Adverse events include those that were reported during the time after the first dose of the study drug until 30 days after the last dose of study drug. The analysis excludes seven participants with genotype information that were randomized but never initiated treatment: three patients in the placebo group, two assigned to 200 mg of celecoxib twice daily, and two assigned to 400 mg of celecoxib twice daily. Data on adverse events include events reported among 639 patients who continued blinded treatment beyond the 36 month core phase of the study who were enrolled in the 24 month extension study.

^bCardiovascular events include cardiovascular death or circulatory collapse, stroke, myocardial infarction, congestive heart failure, venous thrombosis or thromboembolism, cardiovascular therapeutic procedures, vascular therapeutic procedures, cerebrovascular disease, and vascular disease. Four of the cardiovascular events occurred after 36 months. All four of these patients had wild-type genotypes: one patient was randomized to placebo with an event at 38 months; two patients were randomized to 200 mg twice daily with events at 40 and 49 months; one patient was randomized to 400 mg twice daily with an event at 44 months.

^cRenal and hypertensive events include elevated creatinine, fluid retention or edema, hypertension, proteinuria and renal failure. Eighteen of the renal events occurred after 36 months. Eleven patients had wild-type genotypes: 4 patients were randomized to placebo with events at 36.1, 36.4, 38, and 41 months; four patients were randomized to 200 mg twice daily with events at 36.3, 36.6, 36.8, and 36.9 months; three patients were randomized to 400 mg twice daily with events at 36.2, 36.3, and 41 months. Four patients had CYP2C9*2 genotypes: two patients were randomized to placebo with events at 36.1 and 36.4 months; one patient was randomized to 200 mg twice daily with an event at 36.5 months; one patient was randomized to 400 mg twice daily with an event at 41 months. Three patients had CYP2C9*3 genotypes: one patient was randomized to placebo with an event at 36.3 months; two patients were randomized to 400 mg twice daily with events at 36.6 and 36.8 months.

^dGastrointestinal ulceration and hemorrhage events include anemia, gastrointestinal bleeding, gastritis/duodenitis, upper or lower gastrointestinal ulceration, and other hemorrhage. Eleven of the gastrointestinal events occurred after 36 months. Eight patients had wild-type genotypes: three were randomized to placebo with events at 36.3, 36.5, and 37.5 months; three were randomized to 200 mg twice daily with events at 37, 38, and 48 months; two were randomized to 400 mg twice daily with events at 36.7 and 42 months. Two patients had CYP2C9*2 genotypes: one patient was randomized to placebo with an event at 37 months; one patient was randomized to 200 mg twice daily with an event at 36.3 months. One patient had a CYP2C9*3 genotype and was randomized to 400 mg twice daily with an event at 36.6 months.