Lisa M. Wisniewski

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

BACKGROUND The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. RESULTS A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis

BACKGROUND Pain management in patients with osteoarthritis or rheumatoid arthritis often requires long-term use of nonsteroidal antiinflammatory drugs (NSAIDs). However, the relative cardiovascular safety of these therapies remains uncertain. METHODS The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial will evaluate the cardiovascular safety of celecoxib, ibuprofen, and naproxen. Approximately 20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for, or with, established cardiovascular disease will be randomized in this double-blind, triple dummy, multinational, multicenter study. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial will continue until 762 primary events occur with at least 18 months follow-up. Noninferiority of any of the regimens will require a 97.5% upper CI of the hazard ratio (HR) < or =1.33 and point estimate < or =1.12 for both intent-to-treat (ITT) and modified ITT populations. CONCLUSION PRECISION, the first study of patients with high cardiovascular risk chronically treated with a cyclooxygenase-2 selective inhibitor or nonselective NSAID, will define the relative cardiovascular safety profile of celecoxib, ibuprofen, and naproxen and provide data to help guide NSAID use for pain management for this population.

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

Aims Non-steroidal anti-inflammatory drugs (NSAIDs), both non-selective and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely prescribed drugs worldwide, but associate with increased blood pressure (BP) and adverse cardiovascular (CV) events. PRECISION-ABPM, a substudy of PRECISION was conducted at 60 sites, to determine BP effects of the selective COX-2 inhibitor celecoxib vs. the non-selective NSAIDs naproxen and ibuprofen. Methods and results In this double-blind, randomized, multicentre non-inferiority CV-safety trial, 444 patients (mean age 62 ± 10 years, 54% female) with osteoarthritis (92%) or rheumatoid arthritis (8%) and evidence of or at increased risk for coronary artery disease received celecoxib (100–200 mg bid), ibuprofen (600–800 mg tid), or naproxen (375–500 mg bid) with matching placebos in a 1: 1: 1 allocation, to assess the effect on 24-h ambulatory BP after 4 months. The change in mean 24-h systolic BP (SBP) in celecoxib, ibuprofen and naproxen-treated patients was -0.3 mmHg [95% confidence interval (CI), −2.25, 1.74], 3.7 (95% CI, 1.72, 5.58) and 1.6 mmHg (95% CI, −0.40, 3.57), respectively. These changes resulted in a difference of − 3.9 mmHg (P = 0.0009) between celecoxib and ibuprofen, of − 1.8 mmHg (P = 0.12) between celecoxib and naproxen, and of − 2.1 mmHg (P = 0.08) between naproxen and ibuprofen. The percentage of patients with normal baseline BP who developed hypertension (mean 24-h SBP ≥ 130 and/or diastolic BP ≥ 80 mmHg) was 23.2% for ibuprofen, 19.0% for naproxen, and 10.3% for celecoxib (odds ratio 0.39, P = 0.004 and odds ratio 0.49, P = 0.03 vs. ibuprofen and naproxen, respectively). Conclusions In PRECISION-ABPM, allocation to the non-selective NSAID ibuprofen, compared with the COX-2 selective inhibitor celecoxib was associated with a significant increase of SBP, and a higher incidence of new-onset hypertension. ClinicalTrials gov number NCT00346216

Randomised clinical trial: Gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial

To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety.

Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis: A Randomized Clinical Trial

To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long‐term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA).

Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis

To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long‐term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA).

Acute pancreatitis with long-term celecoxib vs. ibuprofen or naproxen: data from the PRECISION trial

To the Editor: We read with interest the paper by Hung et al.[1] “Use of celecoxib correlates with increased relative risk of acute pancreatitis: a case-control study in Taiwan”. The authors found an odds ratio of 5.6 (95% CI 3.33–9.46) for developing acute pancreatitis in subjects taking celecoxib compared with non-users. Their study was not designed to assess whether the coxib associated with a different risk of pancreatitis than non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs). To address that, we examined the database of the PRECISION study: a double-blind controlled trial in 24,081 patients with chronic arthritis, randomized to receive celecoxib 100–200 mg b.i.d., ibuprofen 600–800 mg t.i.d. or naproxen 375–500 mg b.i.d. [2]. All patients were provided with esomeprazole for gastroprotection, and 46% took low-dose aspirin. We searched for all instances of a Serious Adverse Event (essentially events causing death or hospitalization) coded with the terms ‘pancreatitis’ (excluding ‘chronic pancreatitis’) or ‘pancreatic necrosis’ occurring while patients were taking their allocated treatment or up to 30 days afterwards. Mean treatment durations were 20.8, 19.6, and 20.5 months in the celecoxib, ibuprofen, and naproxen groups, respectively. Table 1 lists the numbers who developed acute pancreatitis per treatment arm. There were fewer events in patients randomized to celecoxib than either of the comparators, and the difference compared with naproxen reached statistical significance. Thus the PRECISION data suggest that the risk of developing pancreatitis in patients taking celecoxib is similar or less than that with two commonly used nsNSAIDs. A previous case-control study from Denmark, [3] which compared NSAID use in 3083 pancreatitis cases and >30,000 community controls also found a higher pancreatitis risk in patients taking nsNSAIDs (overall relative risk (RR) 2.7 (95% CI 2.4–3.0)) but not with celecoxib (RR 1.4 (0.8–2.1)) or rofecoxib (1.3 (0.7–2.3). Interestingly, naproxen in the Danish study had the lowest risk among the nsNSAIDs, and not different from the two coxibs (1.1 (0.7–1.7)). So do coxibs carry an increased risk of pancreatitis? The most persuasive evidence from Hung et al.’s study was their finding of a dose-response. However, while they adjusted for known alcoholic diseases, their design did not allow them to adjust for the important risk factors of alcohol intake, tobacco smoking, and obesity. Since there was no placebo arm in PRECISION, we cannot comment directly on the risks of these drugs compared with non-use. However, the incidences we observed can be compared with some population data. A meta-analysis of six studies with data extractable for patients aged ≥40 (mean in PRECISION was 63) gave a pooled incidence of 55 per 100,000 (95% CI 39–72) (data on file)—within the confidence limits we found for celecoxib in PRECISION. The problem with case-control studies is the difficulty of matching all potentially confounding variables, even with adjustments. The best evidence ought to come from RCTs that include a placebo arm, of sufficient size, and duration in patients requiring long-term NSAIDs. However, it is doubtful such a study would be ethical or feasible.

Differences in safety of non-steroidal anti-inflammatory drugs in patients with osteoarthritis and rheumatoid arthritis : a randomized clinical trial

To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long‐term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA).