EBQ:PRECISION

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Study: Nissen et al.. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. The New England journal of medicine 2016. 375:2519-29. PMID: 27959716. DOI.

Clinical Question

Among patients with arthritis requiring daily NSAID therapy and elevated CV risk, is celecoxib noninferior to ibuprofen or naproxen with regard to cardiovascular death, nonfatal MI, and nonfatal stroke?

Bottom Line

Among patients with RA and osteoarthritis and elevated CV risk requiring daily NSAID therapy, celecoxib is noninferior to ibuprofen and naproxen with regard to a primary safety outcome of cardiovascular death, nonfatal MI, and nonfatal stroke after mean follow up of nearly 3 years. Primary outcome events were low (approximately 2-3%) and similar among the three NSAIDs. GI events were significantly lower with celecoxib versus either naproxen or ibuprofen. Renal events were significantly lower with celecoxib versus ibuprofen.

Major Points

NSAIDs are among the most widely prescribed drugs in the world. NSAIDs work by inhibiting cyclooxygenase (COX) which reduces pain and inflammation through inhibition of prostaglandins. Prostaglandins also play an important role in maintaining the gastric mucosa and promoting vasodilation. Inhibition of COX-2 is primarily responsible for pain relief and anti-inflammatory effects while inhibition of COX-1 leads to gastrointestinal toxic effects and may reduce vasodilation. Thus, it is not entirely surprising that the selective COX-2 inhibitors ("coxibs") have demonstrated similar efficacy in pain relief as nonselective COX inhibitors with less GI toxicity in previous trials. However, these trials also suggested possible increases in adverse cardiovascular outcomes with these drugs, presumably by inhibition of protective vasodilating prostaglandins. These early trials only established the possibility of increased events with rofecoxib (now withdrawn from the market) and higher-than-recommended doses of celecoxib. As a result, a more contemporary trial using recommended doses of celecoxib was needed to establish cardiovascular safety of this drug compared to nonselective NSAIDs.

The 2016 Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial randomized 24,081 patients with RA or osteoarthritis requiring daily NSAID therapy and either established CV disease or elevated CV risk to the selective COX-2 inhibitor celecoxib vs. the nonselective NSAIDs naproxen or ibuprofen and assessed for a primary cardiovascular safety outcome of CV death, nonfatal MI, or nonfatal stroke. At mean follow up of 34 months, primary outcome rates were similar across the three treatment arms, with an event rate of 2-3% in each group and established non-inferiority of celecoxib. However, there was a modest 0.5% absolute risk reduction in GI events with celecoxib compared to either ibuprofen or naproxen. There was a 0.4% absolute risk reduction in serious renal events with celecoxib compared to ibuprofen, but no difference compared to naproxen. Arthritis relief was largely similar in magnitude across the three arms, although there was a very modest increase in relief with naproxen relative to ibuprofen or celecoxib. Of note, 69% of patients stopped the study drug during the course of the trial, and 27% discontinued follow-up. However, results were largely unchanged in an on-treatment analysis.

In summary, PRECISION provides high-quality evidence that even in above-average cardiovascular risk patients receiving moderate daily NSAID doses for arthritis, celecoxib is not associated with increased CV events compared to non-selective NSAIDs. As established previously, celecoxib is associated with a significant reduction in GI events compared to ibuprofen or naproxen as well as a reduction in renal events compared to ibuprofen. Given these benefits without an apparent increase in CV events, use of celecoxib is likely to increase even among those with elevated CV risk.

Guidelines

As of March 2017, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, double-blind, noninferiority trial
• N=24,081
  • Celecoxib (N=8072)
  • Naproxen (N=7969)
  • Ibuprofen (N=8040)
• Setting: 926 centers in 13 countries
• Enrollment: October 23, 2006 - June 30, 2014
• Mean follow-up: 34 months
• Analysis: Intention-to-treat
• Primary outcome: CV death, nonfatal MI, nonfatal stroke

Population

Inclusion Criteria

• 18 years of age or older
• Required daily NSAID therapy for RA or osteoarthritis pain
• Established cardiovascular disease or high risk of cardiovascular disease (any of:)
  • Stable angina
  • History of MI, unstable angina, PCI, or CABG at least 3 months prior to trial entry
  • Angiographic coronary or carotid stenosis ≥ 50%
  • TIA or CVA at least 3 months prior to trial entry
  • Symptomatic PAD
  • History of peripheral revascularization procedure
  • Diabetes
  • 3 of the following risk factors concomitantly: Age > 55, HTN, HLD, active smoker, family history of CVD or stroke, microalbuminuria, LVH on ECG or echocardiogram, ABI < 0.9, waist-hip ratio ≥ 0.90

Exclusion Criteria

• Arthritis pain controlled only with acetaminophen

Baseline Characteristics

From the celecoxib group

• Demographics: age 63 years, 64.1% female, 75% white
• Co-morbidities: BMI 32.7, DM 35.2%, HTN 78.0%, HLD 62.9%, smoker 20.9%, creatinine 0.9
• Arthritis type: osteoarthritis 89.9%, rheumatoid arthritis 10.1%, VAS score 54.0
• Medications: aspirin 45.8%, statin 54.1%, DMARD 7.1%

Interventions

• Patients randomized in 1:1:1 ratio to celecoxib, ibuprofen, or naproxen with matching placebo
  • Randomization stratified by baseline ASA use
• Initial doses as follows: celecoxib 100MG BID, ibuprofen 600MG TID, naproxen 375MG BID
• At subsequent visits, for patients with rheumatoid arthritis, investigators could increase to celecoxib 200MG BID, ibuprofen 800MG TID, or naproxen 500MG BID for treatment of symptoms
• Esomeprazole 20-40MG was provided to all patients for gastric protection
• Investigators were encouraged to provide cardiovascular preventive management in accordance with local standards and guidelines (including low-dose ASA if indicated)
• Events reviewed and adjudicated by blinded multidisciplinary specialists at independent contract research organization
• An on-treatment analysis assessed events that occurred while patients were taking the study drug or during the 30 days after discontinuation

Outcomes

Celecoxib vs. naproxen. P-values are for superiority except where specified.

Primary Outcome

Cardiovascular death, nonfatal MI, nonfatal stroke

188 (2.3%) vs. 201 (2.5%) [HR 0.93, 95% CI 0.76-1.13, p=0.45 (superiority), p<0.001 (noninferiority)]

Secondary Outcomes

All-cause mortality

132 (1.6%) vs. 163 (2.0%) [HR 0.80, 95% CI 0.63-1.00, p=0.052]

Major adverse CV events

337 (4.2%) vs. 346 (4.3%) [HR 0.97, 95% CI 0.83-1.12, p=0.64]

Serious GI events

86 (1.1%) vs. 119 (1.5%) [HR 0.71, 95% CI 0.54-0.93, p=0.01]

Renal events

57 (0.7%) vs. 71 (0.9%) [HR 0.79, 95% CI 0.56-1.12, p=0.19]

Celecoxib vs. ibuprofen

Primary Outcome

Cardiovascular death, nonfatal MI, nonfatal stroke

188 (2.3%) vs. 218 (2.7%) [HR 0.85, 95% CI 0.70-1.04, p=0.12 (superiority), p<0.001 (noninferiority)]

Secondary Outcomes

All-cause mortality

132 (1.6%) vs. 142 (1.8%) [HR 0.92, 95% CI 0.73-1.17, p=0.49]

Major adverse CV events

337 (4.2%) vs. 384 (4.8%) [HR 0.87, 95% CI 0.75-1.01, p=0.06]

Serious GI events

86 (1.1%) vs. 130 (1.6%) [HR 0.65, 95% CI 0.50-0.85, p=0.002]

Renal events

57 (0.7%) vs. 92 (1.1%) [HR 0.61, 95% CI 0.44-0.85, p=0.004]

Subgroup Analysis

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

Adverse Events

Celecoxib vs. naproxen

Anemia

221 (2.8%) vs. 331 (4.2%) [p<0.001]

Creatinine increased

148 (1.8%) vs. 154 (1.9%) [p=0.65]

Arthalgia

793 (9.9%) vs. 788 (9.9%) [p=0.90]

HTN

776 (9.7%) vs. 871 (11.0%) [p=0.006]

Celecoxib vs. ibuprofen

Anemia

221 (2.8%) vs.437 (5.5%) [p<0.001]

Creatinine increased

148 (1.8%) vs. 270 (3.4%) [p<0.001]

Arthalgia

793 (9.9%) vs. 679 (8.5%) [p=0.003]

HTN

776 (9.7%) vs. 1039 (13.0%) [p<0.001]

Criticisms

• Due to slow enrollment, higher-than-expected drug discontinuation rate, and lower-than-expected event rate, power to detect noninferiority was only 80%. However, since noninferiority criteria were met, underpowering of the primary outcome does not appear to be a major issue in the study. However, failure to detect differences in secondary outcomes may be related to underpowering.
• High rates of drug discontinuation (68.8%) and study dropout (27.4%) allow for the possibility of informative censoring bias (results biased by asymmetric dropout due to treatment-related factors). However, similar results between the intention-to-treat population and the on-treatment population make significant contribution of this effect to the primary outcome unlikely.
• Study does not provide evidence regarding higher doses of celecoxib (the majority of patients in PRECISION were on 200MG daily), which are used in some patients with more severe arthritis.

Funding

• The trial sponsor participated in the design of the trial and in the writing of the protocol in collaboration with the executive committee and in consultation with the FDA. The sponsor also assisted with data collection and maintained the trial database.