The Cost-Effectiveness of Cyclooxygenase-2 Selective Inhibitors in the Management of Chronic Arthritis

Context Relative to nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors have fewer gastrointestinal complications but cost more. The exact tradeoff between cost and effectiveness is unknown. Contribution This analysis suggests that using rofecoxib and celecoxib rather than naproxen to treat chronic arthritis is cost-effective only for patients with a previous bleeding ulcer or if the cost of COX-2 inhibitors were 10% of its current average wholesale price. Implications At current prices, COX-2 inhibitors offer a cost-effective therapeutic option for treating chronic arthritis only for patients with a previous bleeding ulcer. The Editors Osteoarthritis and rheumatoid arthritis are prevalent and clinically significant health care problems in the United States today, affecting 15% of the population (1), resulting in more than 100 000 hospitalizations per year (2), and consuming nearly 2.5% of the annual gross domestic product when both direct and indirect costs are considered (3). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat chronic arthritis pain, and they account for 3% of the U.S. prescription drug market (4). These agents are a mainstay of treatment despite their association with clinically significant peptic ulcer complications, including symptomatic ulcers, ulcer hemorrhages, and ulcer perforations (5). Moreover, NSAIDs may induce upper-gastrointestinal (GI) dyspeptic symptoms (6, 7), including epigastric pain, bloating, nausea, and heartburn, even in the absence of endoscopic lesions (8). The decision to use NSAIDs to treat patients with chronic arthritis requires a delicate balance between effective pain relief and potential GI complications. Cyclooxygenase-2 selective inhibitors, including rofecoxib and celecoxib (coxibs), have been developed as safer alternatives to nonselective NSAIDs and are widely used in clinical practice. When compared with nonselective NSAIDs, including naproxen and ibuprofen, coxibs achieve equal pain relief while reducing upper GI dyspeptic symptoms by 15% (9) and clinically significant ulcer complications by 50% (10-13). For these reasons, the American Pain Society has recently endorsed coxibs as the drug class of choice for the initial management of moderate to severe arthritis pain, although they cost more than nonselective NSAIDs (14). Despite the significant relative risk reduction in GI complications afforded by coxibs, their absolute risk reduction compared with nonselective NSAIDs is only 1% to 2% for overall ulcer complications and less than 1% for significant ulcer complications (ulcer hemorrhages or perforations) (10-13). In addition, although coxibs reduce GI-related utilization of health care resources compared with nonselective NSAIDs in controlled trials, recent data from clinical practice indicate that patients switching from nonselective NSAIDs to coxibs do not have a concurrent decrease in overall GI-related resource utilization (15, 16). The enthusiasm for coxibs may be further tempered by data suggesting that coxibs are associated with a higher rate of cardiovascular events than nonselective NSAIDs (17). For example, one randomized, controlled trial revealed that for every 333 patients treated with rofecoxib instead of naproxen, there was one additional cardiovascular event, including stroke, unstable angina, or acute myocardial infarction (9). Although the reasoning behind this finding is uncertain and controversial (18), the clinical disparity in significant events was highlighted in a systematic review of coxib trials reporting cardiovascular end points (17). Several U.S. Food and Drug Administration (FDA) reports have also raised this concern (19-21). In light of these data, we sought to determine whether the degree of risk reduction in GI complications seen with coxibs offsets their increased cost compared with generic nonselective NSAIDs in the management of chronic arthritis. We performed an economic analysis to estimate the cost-effectiveness of coxibs versus nonselective NSAIDs in the management of chronic arthritis pain. Methods Decision Model Framework Decision analysis is a quantitative method for estimating the financial costs and clinical outcomes of alternative strategies under conditions of uncertainty (22). By using decision-analysis software (DATA 4.0, TreeAge Software, Inc., Williamstown, Massachusetts), we evaluated two strategies for managing a hypothetical cohort of 60-year-old patients with osteoarthritis or rheumatoid arthritis who were not taking concurrent aspirin and required long-term NSAID therapy for moderate to severe arthritis pain (Figure 1). Patients with a history of ulcer complications were not included in our base-case analysis but were evaluated in a sensitivity analysis. Patients who entered the hypothetical model did not have GI symptoms and were initially treated with either a coxib (celecoxib, 200 mg once daily, or rofecoxib, 25 mg once daily) or a nonselective NSAID at the maximum FDA-approved dose (modeled after naproxen, 500 mg twice daily). Over the course of a lifetime horizon, the patients either developed a GI complication (nonulcer dyspepsia, symptomatic ulcer, ulcer hemorrhage, or ulcer perforation) or remained free of GI adverse events. Patients without complications continued taking their prescribed therapy, and those with complications required further evaluation. To make our model clinically realistic, we required patients to develop symptoms or clinically significant adverse outcomes to prompt further evaluation. We based our assumptions about patient and physician behavior on patient-centered outcomes rather than surrogate end points, such as endoscopic lesions or ulcer healing rates. To capture the full range of downstream costs generated by each strategy, we included the ongoing cost of care associated with GI events and the probability of developing recurrent events over the course of a lifetime in the model. Figure 1. Truncated decision model. A Model Assumptions To systematically bias our analysis in favor of the coxib strategy, we designed our model to explicitly support a study hypothesis that coxibs are more cost-effective than nonselective NSAIDs. This best case model for coxibs was based on four assumptions (Figure 1). First, all patients developing upper-GI dyspeptic symptoms, including epigastric pain, bloating, nausea, or heartburn, were required to undergo upper endoscopy and were prescribed once-daily proton-pump inhibitor (PPI) therapy for the remainder of their lifetimes, regardless of whether an ulcer was identified. Although many patients who develop GI symptoms while taking NSAIDs do not receive endoscopy or long-term PPI therapy, our exaggerated assumption was designed to impart a significant economic penalty for the presence of upper GI symptoms. This assumption economically favors coxibs because they are associated with substantially fewer dyspeptic symptoms than nonselective NSAIDs (9). Second, all patients receiving a nonselective NSAID who developed an upper-GI dyspeptic symptom were also required to discontinue their therapy and switch to a coxib for the remainder of their lifetimes, regardless of whether an ulcer was found on endoscopy. Third, all symptomatic patients found to have an ulcer by upper endoscopy were required to undergo endoscopic biopsy and rapid urease testing for Helicobacter pylori and subsequently received a 14-day course of eradication therapy if positive for H. pylori. Although the role of H. pylori in the pathogenesis of NSAID-related ulcers is controversial (23), we purposely required all patients to be tested and treated for H. pylori to incur an additional economic penalty for the presence of ulcers, therefore biasing the model in favor of coxibs. Finally, although data indicate that nonselective NSAIDs are associated with more GI adverse events than coxibs, a recent FDA review indicates that the incidence of overall serious adverse events is lower with nonselective NSAIDs than with coxibs (7.8% vs. 9.3%) (20). However, to bias our model in favor of coxibs, our base-case analysis included only GI-related adverse events and did not model the observed disparity in adverse events for other organ systems (20). Clinical Data Our base-case model incorporated 23 probability estimates derived from a systematic review of the medical literature (Table 1). We performed a structured search of published reports from the MEDLINE bibliographic databases and hand-searched published abstracts from two major subspecialty journals (Arthritis & Rheumatism and Gastroenterology) to identify English-language publications from January 1985 to December 2002 that pertained to our 23 clinical inputs. We targeted randomized, controlled trials with one or more arms that investigated the use of either nonselective NSAIDs or coxibs in managing chronic arthritis pain and selected trials that reported clinically significant GI complications. Where available, we used summary estimates derived from published systematic reviews and meta-analyses. Where there was a range of data without previous meta-analysis, we used meta-analysis software (RevMan 4.1, Cochrane Collaboration, Oxford, United Kingdom) to establish point estimates for use in the decision tree. Table 1. Base-Case Clinical Probability Estimates Clinical Probability Estimates Upper Gastrointestinal Dyspeptic Symptoms Patients Receiving Nonselective NSAID. Upper-GI dyspeptic symptoms include epigastric pain, bloating, nausea, and heartburn. A recent meta-analysis of randomized, controlled NSAID trials reporting upper-GI dyspeptic symptoms as an outcome derived a pooled prevalence of dyspeptic symptoms of 10.9% in the large exposure studies (sample size > 1000 patients); we adopted this as our base-case value (7). Because the precision of this estimate is unlikely to be reproduced among different populations and may vary with duration of therapy, we varied it from 5% to