Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis

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Original Research

Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis

J Fam Pract. 2002 June;51(6):530-537

By

Alan Kivitz, MD

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References

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ABSTRACT

OBJECTIVE: We compared the efficacy and upper gastrointestinal safety of the cyclooxygenase-2–specific inhibitor valdecoxib with naproxen and placebo in treating moderate to severe osteoarthritis of the knee.

STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and upper gastrointestinal tract safety of valdecoxib at dosages of 5, 10, and 20 mg once daily with placebo and naproxen at the dosage of 500 mg twice daily.

POPULATION: We included patients who had been diagnosed with moderate to severe osteoarthritis of the knee according to the modified criteria of the American College of Rheumatology.

OUTCOMES MEASURED: The Patient’s and Physician’s Global Assessment of Arthritis (PaGAA, PhGAA), Patient’s Assessment of Arthritis Pain–Visual Analog Scale (PAAP-VAS), and Western Ontario and McMaster’s Universities (WOMAC) Osteoarthritis indices were assessed at baseline and at weeks 2, 6, and 12. Upper gastrointestinal ulceration was assessed by pre- and posttreatment endoscopies.

RESULTS: Valdecoxib 10 and 20 mg once daily (but not 5 mg once daily) demonstrated similar efficacy to naproxen at 500 mg twice daily, and all 3 dosages were superior to placebo for the PaGAA, PhGAA, PAAP-VAS, and WOMAC Osteoarthritis indices at most assessments throughout the 12-week study (P < .05). The incidence of endoscopically proven ulcers was significantly higher in the naproxen group than in the 5- and 10-mg valdecoxib groups, but not in the 20-mg valdecoxib group. All 3 valdecoxib doses were comparable to placebo in ulcer incidence.

CONCLUSIONS: Valdecoxib (10 and 20 mg once daily) is significantly superior to placebo and as effective as naproxen (500 mg twice daily) in improving moderate to severe osteoarthritis of the knee. Upper gastrointestinal tract safety of valdecoxib (5 and 10 mg) was comparable to that of placebo and significantly better than that of naproxen.

KEY POINTS FOR CLINICIANS

The cyclooxygenase-2–specific inhibitor valdecoxib 10 or 20 mg once daily is as effective as naproxen 500 mg twice daily.
Valdecoxib at the recommended dose for treatment of osteoarthritis (10 mg once daily) had better upper gastrointestinal safety than naproxen.

Current medical therapies for osteoarthritis include conventional nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, glucosamine sulfate, and intra-articular injections of corticosteroids and hyaluronic acid. However, long-term use of corticosteroid injections can exacerbate damage to the affected joints.1,2 Conventional NSAIDs are associated with upper gastrointestinal tract ulceration and inhibition of platelet function.3

Cyclooxygenase-2 (COX-2)–specific inhibitors have demonstrated equivalent efficacy to conventional NSAIDs in treating pain and inflammation associated with osteoarthritis and rheumatoid arthritis. Further, COX-2–specific inhibitors significantly reduce the incidence of gastrointestinal ulceration and bleeding side effects caused by conventional NSAIDs.^4,5 Valdecoxib (Bextra; Pharmacia Corporation and Pfizer Corporation) is a novel COX-2–specific inhibitor that is approximately 28,000-fold more selective against COX-2 than against COX-1. As a potent COX-2–specific inhibitor, valdecoxib is expected to provide efficacy equivalent to conventional NSAIDs for treatment of arthritis and spare the COX-1–related side effects. This randomized, placebo-controlled, double-blind, 12-week study was designed to test this hypothesis by comparing the efficacy and upper gastrointestinal tract safety of valdecoxib with that of naproxen, a leading conventional NSAID comparator.

Methods

Study population

Ambulatory adults who had been diagnosed with moderate to severe osteoarthritis of the knee according to the modified criteria of the American College of Rheumatology^6,7 were eligible to participate in the trial. Patients were recruited from primary care and rheumatology specialty settings. Patients who had baseline scores of at least 40 mm on the Patient’s Assessment of Arthritis Pain–Visual Analog Scale (PAAP-VAS) and baseline categorical scores of poor to very poor on the Patient’s (PaGAA) and Physician’s (PhGAA) Global Assessments of Arthritis were included.^8,9 Any patient suffering from inflammatory arthritis, gout, pseudogout, Paget disease, or any chronic pain syndrome that might interfere with assessment of the Index Knee was excluded from the trial. Patients diagnosed with osteoarthritis of the hip ipsilateral to the Index Knee, severe anserine bursitis, acute joint trauma, or complete loss of articular cartilage on the Index Knee also were excluded. Patients were not eligible if they had active gastrointestinal disease, gastrointestinal tract ulceration 30 days before the trial, a significant bleeding disorder, or a history of gastric or duodenal surgery. Patients with an esophageal, gastric, pyloric channel, or duodenal ulcer or a score of at least 10 for esophageal, gastric, or duodenal erosions at the pretreatment endoscopy examination also were excluded.

FIGURE 1
Patient’s global assessment of arthritis

Study design

This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and upper gastrointestinal tract safety of valdecoxib at dosages of 5, 10, and 20 mg once daily with placebo and naproxen at a dosage of 500 mg twice daily in relieving moderate to severe osteoarthritis of the knee. The trial was conducted in 85 centers in the United States and Canada, in accordance with the principles of good clinical practice and the Declaration of Helsinki. Eligible patients were randomized to treatment groups and self-administered oral study medication. Patients were randomized to study treatment in the order in which they were enrolled into the study by using a treatment sequence that was determined by a Searle-prepared computer-generated randomization schedule. Patients received their allocated study medications in bottles labeled A and B according to the randomization schedule. Personnel at the study centers carried out the assessments and remained blinded throughout the study. Eligible patients were enrolled and discontinued regular pain medication. Patients discontinued their normal medications at the following specified times before the baseline endoscopy: NSAIDs (including full-dose aspirin at a dosage of ≥325 mg/day) at 48 hours, corticosteroid injections at 4 weeks, and intra-articular injections of corticosteroid or hyaluronic acid preparations at 3 and 6 months, respectively. The use of antiulcer drugs, including H2 blockers, proton pump inhibitors, misoprostol, and sucralfate, was discontinued at least 24 hours before the baseline endoscopy.