Prospective Randomized Evaluation of Celeboxib Integrated Safety Versus Ibuprofen or Naproxen - PRECISION

Contribution To Literature:

The PRECISION trial showed similar cardiovascular safety of celecoxib compared with ibuprofen or naproxen.

Description:

The goal of the trial was to evaluate the cardiovascular safety of celecoxib compared with ibuprofen or naproxen among patients with arthritis and increased cardiovascular risk requiring treatment with a nonsteroidal anti-inflammatory drug (NSAID).

Study Design

  • Randomized
  • Parallel
  • Blinded
  • Stratified

Patients with arthritis and increased cardiovascular risk were randomized to celecoxib 100 mg twice daily (n = 8,072) versus ibuprofen 600 mg three times daily (n = 8,040) versus naproxen 375 mg twice daily (n = 7,969). Patients with rheumatoid arthritis could up-titrate their study medication if needed at follow-up visit (celecoxib 200 mg twice daily, ibuprofen 800 mg three times daily, or naproxen 500 mg twice daily).

  • Total number of enrollees: 24,081
  • Duration of follow-up: mean 34 months (mean treatment duration 20 months)
  • Mean patient age: 63 years
  • Percentage female: 64%
  • Percentage with diabetes: 35%

Inclusion criteria:

  • Patients ≥18 years of age with osteoarthritis or rheumatoid arthritis requiring treatment with a NSAID
  • Established cardiovascular disease or increased risk for cardiovascular disease

Exclusion criteria:

  • Patients whose arthritis pain was managed adequately with acetaminophen

Other salient features/characteristics:

  • Patient risk category (primary prevention 77%, secondary prevention 23%)
  • During follow-up, 69% of patients stopped study drug

Principal Findings:

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 2.3% of the celecoxib group vs. 2.7% of the ibuprofen group vs. 2.5% of the naproxen group (hazard ratio [HR] 0.85, pnoninferiority < 0.001 for celecoxib vs. ibuprofen; HR 0.93, pnoninferiority < 0.001 for celecoxib vs. naproxen; HR 1.08, pnoninferiority = 0.02 for ibuprofen vs. naproxen). Findings were the same with subgroup analysis and on-treatment analysis.

Secondary outcomes:

  • All-cause mortality: 1.6% for celecoxib, 1.8% for ibuprofen, 2.0% for naproxen
  • For NSAID use and all-cause mortality, there appeared to be effect modification according to presence of osteoarthritis or rheumatoid arthritis: There was no difference in the hazard of all-cause mortality between the study groups among those with osteoarthritis; however, among those with rheumatoid arthritis, naproxen was associated with the highest hazard of all-cause mortality.
  • Gastrointestinal  (GI) events: 1.1% for celecoxib, 1.6% for ibuprofen, 1.5% for naproxen (HR 0.65, p = 0.002 for celecoxib vs. ibuprofen, HR 0.71, p = 0.01 for celecoxib vs. naproxen)
  • Renal events: 0.7% for celecoxib, 1.1% for ibuprofen, 0.9% for naproxen (HR 0.61, p = 0.004 for celecoxib vs. ibuprofen, HR = 0.79, p = 0.19 for celecoxib vs. naproxen)
  • All-cause mortality, clinical GI events, iron deficiency anemia of GI origin, renal events, or hospitalization for hypertension or congestive heart failure (on-treatment analysis): HR 0.81, pnoninferiority < 0.001 for celecoxib vs. ibuprofen; HR 0.90, pnoninferiority < 0.001 for celecoxib vs. naproxen; HR 1.12, pnoninferiority < 0.025 for ibuprofen vs. naproxen

PRECISION-ABPM substudy: Among those who underwent ambulatory blood pressure monitoring (ABPM), change in systolic blood pressure from baseline to 4 months was -0.3 mm Hg in the celecoxib group, 3.7 mm Hg in the ibuprofen group, and 1.6 mm Hg in the naproxen group. Patients who developed hypertension during the course of the study included 10% in the celecoxib group, 23% in the ibuprofen group, and 19% in the naproxen group.

Interpretation:

Among patients with arthritis (osteoarthritis or rheumatoid arthritis) and increased cardiovascular risk, modest-dose celecoxib was noninferior to ibuprofen or naproxen in regard to cardiovascular safety. Secondary findings documented fewer GI events for celecoxib compared with ibuprofen or naproxen, and fewer renal events for celecoxib compared with ibuprofen. Ibuprofen was associated with the largest increase in mean systolic blood pressure at 4 months. Overall, there appeared to be less toxicity with celecoxib compared with ibuprofen or naproxen. Limitations of the trial include very high study discontinuation (69%) and an overall low event rate (77% did not have established cardiovascular disease).

A second important finding of the trial is dispelling the notion that naproxen is the safest nonselective NSAID. This trial demonstrated similar overall cardiovascular events for ibuprofen versus naproxen. In fact, all-cause mortality was numerically highest in the naproxen group, which appeared to be exaggerated among those with rheumatoid arthritis.

References:

Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J 2017;Aug 28:[Epub ahead of print].

Presented by Dr. Steven E. Nissen at the European Society of Cardiology Congress, Barcelona, Spain, August 29, 2017.

Presented by Dr. Frank Ruschitzka at the European Society of Cardiology Congress, Barcelona, Spain, August 28, 2017.

Nissen SE, Yeomans ND, Solomon DH, et al., on behalf of the PRECISION Trial Investigators. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016;375:2519-29.

Editorial: FitzGerald GA. Imprecision: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation 2017;135:113-15.

Presented by Dr. Steven E. Nissen at the American Heart Association Annual Scientific Sessions (AHA 2016), New Orleans, LA, November 13, 2016.

Clinical Topics: Acute Coronary Syndromes, Prevention, Stable Ischemic Heart Disease, Chronic Angina

Keywords: ESC2017, ESC Congress, Acute Coronary Syndrome, AHA Annual Scientific Sessions, Angina, Stable, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Rheumatoid, Blood Pressure, Blood Pressure Monitoring, Ambulatory, Cardiovascular Diseases, Cyclooxygenase Inhibitors, Gastrointestinal Tract, Ibuprofen, Myocardial Infarction, Naproxen, Osteoarthritis, Primary Prevention, Pyrazoles, Renal Insufficiency, Risk Factors, Stroke


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