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- APPENDIX A
Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly used medications for chronic arthritis, accounting for 111 million prescriptions annually and 3% of the American prescription drug market (1, 2). These agents continue to serve as the mainstay of treatment despite their association with clinically significant gastrointestinal (GI) complications, including nonulcer dyspepsia, symptomatic ulcers, ulcer hemorrhages, and ulcer perforations (3). The economic impact of these adverse events is significant: they result in >100,000 hospitalizations annually at a cost of $1.6 billion (1, 4). Moreover, each year there are 17,000 deaths in the United States as a result of NSAID-related GI complications (1). In light of the substantial human and economic costs of NSAID-related adverse events, the decision to use NSAIDs requires a delicate balance between effective pain relief on the one hand and GI complications on the other.
However, the optimal therapeutic strategy is not dictated by generic decision rules, but rather is guided by consideration of individual risk factors (5). In particular, the risk of developing NSAID-related GI complications is highest among patients taking concurrent aspirin, coumadin, or steroids; patients with a previous history of an ulcer hemorrhage; and patients >65 years of age (5, 6). Moreover, the prevalence of these risk groups has increased significantly in lockstep with the aging of the American population and the increasing use of aspirin for cardioprophylaxis. In light of these clinical data and epidemiologic trends, there is an increasing need to develop strategies that minimize adverse events while effectively treating the burgeoning population of high-risk patients with chronic arthritis.
Cyclooxygenase 2-selective inhibitors, including rofecoxib and celecoxib (coxibs), have been developed to fill the need for a safer alternative to the traditional nonselective NSAID (NSAIDNS). When compared with NSAIDNS agents, including naproxen and ibuprofen, coxibs achieve equal arthritis pain relief while reducing clinically significant ulcer complications by 50% (7–10). For these reasons, coxibs are now widely used in clinical practice, and at least one professional society has endorsed coxibs as the drug class of choice for the initial management of moderate-to-severe arthritis pain (11).
Despite the enthusiasm for coxibs, emerging data suggest that alternative therapies may be equally or more preferable, including the use of an NSAIDNS alone or in combination with a proton pump inhibitor (PPI). In particular, 5 findings cast uncertainty regarding the endorsement of coxibs in lieu of these alternative therapies: 1) despite the significant relative risk reduction in GI complications afforded by coxibs, their absolute risk reduction compared with NSAIDNS is <1% for significant ulcer complications (7–10); 2) recent economic models reveal that the small degree of risk reduction is insufficient to offset the increased cost of coxibs versus generic NSAIDs for average-risk patients (12, 13); 3) prospective studies in high-risk patients indicate that coxibs do not provide an additional risk reduction when compared with the NSAIDNS + PPI combination (14, 15); 4) data reveal that the use of concurrent aspirin attenuates the relative GI protective effects of coxibs versus NSAIDNS (9); and 5) 1 randomized controlled trial (Vioxx gastrointestinal outcomes research [VIGOR] trial) revealed a significantly increased risk for cardiovascular events with rofecoxib versus naproxen (7).
These circumstances raise questions regarding the cost-effective use of coxibs in patient populations eligible for aspirin prophylaxis with various degrees of GI and cardiovascular risk. Previous decision analyses have demonstrated that coxibs may be cost-effective in patients at high risk for GI complications (12, 13, 16–19). However, these models generally have focused on a limited number of competing strategies, have not allowed for the use of concurrent aspirin, have not evaluated varying combinations of GI and cardiovascular risks simultaneously, and have not incorporated model flexibility to account for varying management decisions as a function of individual risk.
In light of these new data and uncertainties, we sought to reappraise the initial treatment of choice for arthritis patients with varying risk factors. We therefore performed a comprehensive economic model to estimate the cost-effectiveness of 3 competing strategies: 1) NSAIDNS alone, 2) NSAIDNS + PPI, and 3) coxib alone. We designed our analysis to account for both GI and cardiovascular risk factors in a cohort of patients eligible for aspirin prophylaxis, and structured the model to reflect the clinical reality that management decisions are conditional upon individual risk profiles.
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- APPENDIX A
This analysis of therapies in the management of chronic arthritis suggests that the optimal strategy is highly dependent upon individual risk factors. For patients at average risk for an NSAID-related GI complication, the analysis supports the finding of previous models that the use of generic nonselective NSAIDs is optimally cost-effective. Specifically, the analysis reveals that the substitution of either a coxib or an NSAIDNS + PPI combination in lieu of generic naproxen may cost >$300,000 more per QALY gained in average-risk patients—a cost that is significantly higher than most accepted interventions in medicine. However, in patients with one or more risk factors for a GI event (age >65 years, taking coumadin or steroids, previous ulcer complication), the unprotected use of NSAIDNS alone is dominated by the NSAIDNS + PPI strategy.
Our analysis indicates that the use of coxibs alone may not be cost-effective compared with the NSAIDNS + PPI strategy. These findings emerge despite explicitly biasing the model against the NSAIDNS + PPI strategy and in favor of the coxib strategy. Four assumptions, in particular, exemplify this bias: 1) rather than assume that PPIs reduce clinically significant ulcer complications by up to 80%, as suggested by the literature (14, 28–31), we instead adopted a 50% risk reduction as our base-case estimate; 2) rather than assume that PPIs reduce nonulcer dyspepsia by 50%, as suggested by meta-analysis (Figure 2), we instead adopted an 18% risk reduction (representing the lower 95% CI from the meta-analysis); 3) rather than assume that up to 50% of the hypothetical 60-year-old cohort was eligible for cardioprophylaxis, as suggested by current guidelines (23), we assumed that only 20% received aspirin cotherapy—an assumption that favors coxibs given their attenuated gastroprotection when used with aspirin (9); and 4) rather than assume that the incidence of overall serious adverse events is lower with nonselective NSAIDs than coxibs, as indicated by an FDA review measuring outcomes across all organ systems (7.8% versus 9.3%) (49), our analysis only included GI adverse events and did not model the observed disparity in adverse events for other organ systems (e.g., renal effects, heart failure, etc.). Despite these assumptions, the coxib strategy was less effective and more expensive than the NSAIDNS + PPI combination.
This finding partly results from 2 key assumptions regarding coxibs: 1) the assumption that coxibs may be associated with a higher rate of cardiovascular events than NSAIDNS agents such as naproxen (7, 45), and 2) the assumption that aspirin cotherapy may partially mitigate the gastroprotective effects of coxibs. In acknowledgement of the controversy and uncertainty surrounding the first assumption, we performed a separate analysis assuming equal rates of cardiovascular events across all strategies. Despite this favorable assumption for coxibs, however, the NSAIDNS + PPI combination remains dominant over the coxib strategy. Nonetheless, firm conclusions regarding these exploratory data cannot be drawn until further well-designed prospective trials are conducted to evaluate the cardiovascular effects of coxibs. In the meantime, decision making should proceed with a keen awareness of the impact that potential variations in cardiovascular safety may have on overall effectiveness and cost-effectiveness.
Our assumption that aspirin partially mitigates the ability of coxibs to reduce ulcer complications versus generic NSAIDs is controversial. Nonetheless, it is based upon the only fully published randomized prospective trial to date reporting clinically significant ulcer complications in patients receiving coxib + ASA versus NSAIDNS + ASA (CLASS study) (9). Of note, sensitivity analysis of our model indicates that coxibs gain in cost-effectiveness when the CLASS data are disregarded. However, until prospective data from well-designed trials are collected that contradict the observation in CLASS, there will be insufficient evidence to conclude that coxibs are cost-effective in the increasingly large population of patients who are candidates for aspirin cardioprophylaxis.
Our study has several unique features compared with previous economic analyses for NSAID use in arthritis (12, 16–19, 53–55). First, whereas previous models focus on the selected subgroup of patients not eligible for aspirin cardioprophylaxis, this analysis allows for the use of concurrent aspirin, and therefore attempts to reflect clinical practice. Second, whereas most analyses compare the use of an NSAIDNS versus one “safer” strategy (e.g., coxib, nabumetone, NSAIDNS + misoprostal) (53, 55), this analysis focuses on the role of PPI coprescription to address a currently debated option available in the primary care setting. Third, whereas previous models are designed as rigid trees that manage patients similarly regardless of individual risk, this model incorporates flexibility through the use of conditional logic nodes to account for varying management decisions as a function of patient risk. Last, whereas previous models handle areas of uncertainty by imputing data based on the authors' best estimates, this analysis relied upon a multidisciplinary panel of 9 expert physicians to judge uncertain estimates, and elicited these estimates through an explicit and reproducible process (Delphi technique).
There are also several limitations to the present study. As with any decision analysis, the results depend upon the validity of the base-case estimates. Because our base-case point estimates are largely derived from randomized controlled trials and expert opinion, our findings may not be generalizable to all relevant arthritis populations. Moreover, several of our estimates are based on studies of varying design, patient population, followup, and quality. However, we attempted to guard against inaccurate base-case results by systematically reviewing the literature, relying on preexisting meta-analyses when available, and conducting our own meta-analyses when necessary to develop precise point estimates. In addition, we relied upon an expert panel of physicians to provide estimates in areas in which data are lacking. In circumstances where clinical data are incomplete, the National Panel for Cost-Effectiveness in Health and Medicine suggests that estimates should be developed on the basis of extrapolation and imputation of the best available evidence and theory (50). In this regard, the National Panel considers this method of estimation to be “a valid form of scientific inquiry.” We therefore believe that our exploratory analysis is based upon the best-available data.
In conclusion, this analysis reveals that the cost-effectiveness of competing NSAID strategies in chronic arthritis is highly dependent on individual risk factors. Our analysis suggests that generic nonselective NSAIDs are most cost-effective in patients at low risk for an adverse event. However, as both the GI and cardiovascular risk increase, the addition of a PPI to a nonselective NSAID may be preferable to coxib-based strategies. We therefore suggest that the cost-effectiveness of these competing strategies be reappraised with additional prospective trials comparing the accrued cost and effectiveness across a range of risk profiles.