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PRECISION

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

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Year of Publication: 2016

Authors: Steven E. Nissen, M.D., Neville D. Yeomans, ..., and A. Michael Lincoff

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2016;375:2519-29.

Link: https://doi.org/10.1056/NEJMoa1611593

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1611593

Clinical Question

In patients with arthritis at increased cardiovascular risk, is the cardiovascular safety of moderate-dose celecoxib noninferior to that of naproxen or ibuprofen?

Bottom Line

At moderate doses, celecoxib was noninferior to both naproxen and ibuprofen with regard to cardiovascular safety. Celecoxib was associated with a lower risk of gastrointestinal events than both comparators and a lower risk of renal events than ibuprofen.

        Major Points
        The PRECISION trial was a large, randomized, double-blind, noninferiority trial comparing the cardiovascular safety of celecoxib, naproxen, and ibuprofen. 
The study enrolled 24,081 patients with osteoarthritis or rheumatoid arthritis who were at increased cardiovascular risk. 
The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. 
In the intention-to-treat analysis, celecoxib was noninferior to naproxen (HR 0.93; 95% CI, 0.76 to 1.13) and ibuprofen (HR 0.85; 95% CI, 0.70 to 1.04). 
The risk of major gastrointestinal events was significantly lower with celecoxib compared to both naproxen (P=0.01) and ibuprofen (P=0.002). 
The risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but not significantly different from naproxen. 

      

Design

Study Type: Randomized, multicenter, double-blind, noninferiority trial.

Randomization: 1

Blinding: Double-blind.

Enrollment Period: October 23, 2006, to June 30, 2014.

Follow-up Duration: Mean follow-up period of 34.1 ± 13.4 months.

Centers: 926

Countries: 13 countries, unspecified

Sample Size: 24081

Analysis: Intention-to-treat and on-treatment populations.

Inclusion Criteria

Age 18 years or older.
Required daily treatment with NSAIDs for arthritis pain (osteoarthritis or rheumatoid arthritis).
Established cardiovascular disease or an increased risk of the development of cardiovascular disease.

Exclusion Criteria

Patients whose arthritis pain was managed adequately with acetaminophen.
Other unspecified exclusion criteria are provided in the protocol.

Baseline Characteristics

Characteristic	Control	Active
Age-yr	63.3±9.4	63.0±9.5
Female sex no. (%)	5096 (63.9)	5175 (64.1)
Race (White)-no. (%)	5926 (74.4)	6058 (75.0)
Race (Black)-no. (%)	1134 (14.2)	1090 (13.5)
Body-mass index	32.6±7.3	32.7±7.3
Primary arthritis diagnosis (Osteoarthritis)-no. (%)	7178 (90.1)	7259 (89.9)
Primary arthritis diagnosis (Rheumatoid arthritis)-no. (%)	791 (9.9)	813 (10.1)
Current aspirin use - no. (%)	3652 (45.8)	3701 (45.8)
Cardiovascular risk category (Primary prevention)-no. (%)	6186 (77.6)	6209 (76.9)
Cardiovascular risk category (Secondary prevention)-no. (%)	1783 (22.4)	1863 (23.1)
History of diabetes-no. (%)	2768 (34.7)	2843 (35.2)
History of hypertension-no. (%)	6145 (77.1)	6296 (78.0)
History of dyslipidemia-no. (%)	4966 (62.3)	5080 (62.9)
Current smoker-no. (%)	1631 (20.5)	1689 (20.9)
Current statin use-no. (%)	4304 (54.0)	4367 (54.1)
Systolic blood pressure-mm Hg	125.0±10.6	125.3±10.5
Diastolic blood pressure-mm Hg	75.4±8.0	75.5±8.0
Creatinine level-mg/dl	0.9±0.72	0.9±0.23
VAS score-mm	54.1±24.0	54.0±23.5

Arms

Field	Control	Celecoxib (Active)	Ibuprofen
Intervention	Naproxen at a mean daily dose of 852±103 mg. All patients were also provided esomeprazole for gastric protection.	Celecoxib at a mean daily dose of 209±37 mg. All patients were also provided esomeprazole for gastric protection.	Ibuprofen at a mean daily dose of 2045±246 mg. All patients were also provided esomeprazole for gastric protection.
Duration	Mean treatment duration of 20.3±16.0 months.	Mean treatment duration of 20.3±16.0 months.	Mean treatment duration of 20.3±16.0 months.

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
The primary composite outcome was the first occurrence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke (APTC criteria).	Primary	2.5% (201 patients)	2.3% (188 patients)	0.93	<0.001 for noninferiority
Major adverse cardiovascular events (Primary outcome + revascularization or hospitalization for unstable angina/TIA)	Secondary	4.3% (346 patients)	4.2% (337 patients)	HR 0.97 (95% CI, 0.83 to 1.12)	0.64
Death from any cause	Secondary	2.0% (163 patients)	1.6% (132 patients)	HR 0.80 (95% CI, 0.63 to 1.00)	0.052
Composite of serious gastrointestinal events	Adverse	1.5% (119 patients)	1.1% (86 patients)	HR 0.71 (95% CI, 0.54 to 0.93)	0.01
Renal events	Adverse	0.9% (71 patients)	0.7% (57 patients)	HR 0.79 (95% CI, 0.56 to 1.12)	0.19
Hospitalization for hypertension	Adverse	0.5% (40 patients)	0.3% (24 patients)	HR 0.69 (95% CI, 0.41 to 1.17)	0.17

Subgroup Analysis

The analyses of the primary composite outcome among prespecified subgroups showed no significant interactions for any pairwise comparison, including for aspirin use at baseline.

Criticisms

Adherence and retention were lower than in most cardiovascular outcomes trials, which makes interpretation of the findings challenging.
The large number of comparisons without adjustment for multiplicity increases the possibility of false positive findings.
The dose of celecoxib was limited to a moderate dose (mean 209 mg daily), so results may not apply to higher doses.
The trial did not include a placebo comparison group, so no inferences can be made regarding the absolute safety of NSAIDs.
The results reflect the relative safety of only celecoxib, ibuprofen, and naproxen and cannot be extrapolated to other NSAIDs.

Funding

Pfizer.

Based on: PRECISION (The New England Journal of Medicine, 2016)

Authors: Steven E. Nissen, M.D., Neville D. Yeomans, ..., and A. Michael Lincoff

Citation: N Engl J Med 2016;375:2519-29.

Content summarized and formatted by NeuroTrials.ai.

PRECISION

(2016)

Objective

To assess cardiovascular safety of celecoxib compared to ibuprofen or naproxen in patients with arthritis and elevated cardiovascular risk.

Study Summary

• Celecoxib was noninferior to ibuprofen and naproxen for major cardiovascular events in patients with arthritis and elevated CV risk; • Celecoxib had lower GI and renal event rates compared to ibuprofen.

Intervention

Celecoxib (100–200 mg BID), ibuprofen (600–800 mg TID), or naproxen (375–500 mg BID) plus esomeprazole for GI protection. Patients followed up for mean 34 months.

Inclusion Criteria

Adults with osteoarthritis or rheumatoid arthritis needing NSAIDs and at increased cardiovascular risk. Excluded if well-controlled on acetaminophen or with contraindications.

Study Design

Arms: Celecoxib vs. Ibuprofen vs. Naproxen

Patients per Arm: Celecoxib: 8072, Naproxen: 7969, Ibuprofen: 8040

Outcome

• Primary outcome (APTC: CV death, MI, stroke): 2.3% celecoxib vs. 2.5% naproxen vs. 2.7% ibuprofen. <br>• Celecoxib noninferior to both. <br>• Lower GI and renal event rates vs. ibuprofen..

Bottom Line

Major Points

The PRECISION trial was a large, randomized, double-blind, noninferiority trial comparing the cardiovascular safety of celecoxib, naproxen, and ibuprofen.
The study enrolled 24,081 patients with osteoarthritis or rheumatoid arthritis who were at increased cardiovascular risk.
The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
In the intention-to-treat analysis, celecoxib was noninferior to naproxen (HR 0.93; 95% CI, 0.76 to 1.13) and ibuprofen (HR 0.85; 95% CI, 0.70 to 1.04).
The risk of major gastrointestinal events was significantly lower with celecoxib compared to both naproxen (P=0.01) and ibuprofen (P=0.002).
The risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but not significantly different from naproxen.

Study Design

Study Type: Randomized, multicenter, double-blind, noninferiority trial.
Randomization: Yes
Blinding: Double-blind.
Sample Size: 24081
Follow-up: Mean follow-up period of 34.1 ± 13.4 months.
Centers: 926
Countries: 13 countries, unspecified

Primary Outcome

Definition: The primary composite outcome was the first occurrence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke (APTC criteria).

Control	Intervention	HR/OR	P-value
2.5% (201 patients)	2.3% (188 patients)	0.93 (0.76 to 1.13)	<0.001 for noninferiority

Limitations & Criticisms

Adherence and retention were lower than in most cardiovascular outcomes trials, which makes interpretation of the findings challenging.
The large number of comparisons without adjustment for multiplicity increases the possibility of false positive findings.
The dose of celecoxib was limited to a moderate dose (mean 209 mg daily), so results may not apply to higher doses.
The trial did not include a placebo comparison group, so no inferences can be made regarding the absolute safety of NSAIDs.
The results reflect the relative safety of only celecoxib, ibuprofen, and naproxen and cannot be extrapolated to other NSAIDs.

Citation

N Engl J Med 2016;375:2519-29.

View Original Publication →

PRECISION

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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