Since the introduction of aspirin ... REPORTS... Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care. A.

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1 ... REPORTS... Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care A. Mark Fendrick, MD Abstract The gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established. The management of patients requiring NSAID therapy has been revolutionized by the cyclooxygenase (COX)-2 inhibitors (coxibs), equally efficacious agents that significantly reduce GI complications. The safety advantage of coxibs comes at the expense of higher drug acquisition costs. To make informed decisions regarding the value of these added expenditures, a careful analysis of the clinical and economic impact of these new agents is warranted. This article focuses on the issues pertinent to healthcare payers as they evaluate the coxibs, and provides a review of the studies that calculate the cost-effectiveness of these innovative drugs in a number of patient populations and health systems. (Am J Manag Care. 2002;8:S529-S541) Since the introduction of aspirin more than 100 years ago, nonsteroidal anti-inflammatory drugs (NSAIDs) have grown to become one of the most widely used classes of medications. Both prescription and over-thecounter (OTC) preparations are available in a variety of doses and formulations. Prior to the introduction of cyclooxygenase (COX)-2 inhibitors (coxibs), the market for prescription NSAIDs in the United States alone approached $2 billion in sales annually 1 ; OTC sales have contributed another $2 billion. 2,3 The reason for the widespread use of these agents lies in the demonstrated analgesic and anti-inflammatory efficacy of these drugs. They are recommended for a variety of conditions, including postoperative pain, low back pain, osteoarthritis (OA), rheumatoid arthritis (RA), and cancer pain, for which they are included in the first rung of the World Health Organization analgesic ladder. 4 Although much of their use is for acute conditions, chronic use is common, especially among patients with OA and RA. The gastrointestinal (GI) toxicity of NSAIDs is well described. Adverse effects range from mild dyspeptic symptoms to serious GI events such as perforation and hemorrhage. These adverse events are of importance not only in terms of the resultant morbidity and mortality; they also incur substantial resource use. The costs to treat GI adverse events and those interventions aimed to prevent their occurrence have been estimated in population-based studies to account for at least one third of the total medical expenditures for patients being treated for arthritis. 5 These direct medical expenditures, however, likely underestimate the total economic burden of NSAID-induced GI complications, because they do not account for the indirect costs resulting from lost productivity and premature death that also have an effect from a societal perspective. Numerous clinical strategies have been suggested to reduce the risk of GI events (Table). 6-8 Each of these strategies trades off clinical benefit in terms of efficacy (symptom relief) and side effects; there are clear advantages and disadvantages of each. At present no optimal management approach exists; no approach simultaneously and universally yields high levels of analgesia and anti-inflammatory VOL. 8, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S529

2 REPORTS Table. Management Strategies for the Prevention of NSAID-Associated Gastropathy Strategy Discontinue NSAID Clinical Disadvantage Loss of efficacy Use a non-nsaid analgesic (eg, acetaminophen) Acetaminophen not effective in all patients 6 Decrease NSAID dose Potential loss of efficacy Use a safer but equally effective NSAID Interpatient variability in efficacy and tolerability Use gastroprotective agents: misoprostol; Increased polypharmacy may lead to reduced compliance H 2 -receptor antagonist; proton pump inhibitor Associated with side effects (high incidence of diarrhea) 7 Ineffective at traditional doses 8 High acquisition costs NSAID indicates nonsteroidal anti-inflammatory drug. activity with no undesirable outcomes. The unwanted results may either directly affect the patients (side effects) or be incurred by the payers (high cost of safer drug regimens). The introduction of the coxibs (celecoxib, rofecoxib, and valdecoxib) has added an important new management option to reduce the clinical and economic burden of NSAID-induced GI events. As discussed elsewhere in this supplement, these agents have similar efficacy and an improved GI safety profile when compared with traditional NSAIDs (in the absence of low-dose aspirin). Their availability changed the paradigm of management of patients requiring NSAIDs, particularly individuals with an increased risk of an NSAID-related GI adverse event. This clinical advantage comes at the expense of the increased acquisition cost of the coxibs when compared with traditional NSAIDs. This increased cost raises concern whether the improved GI safety is worth the added expenditures on the drugs themselves. This issue is of paramount importance as managed care organizations and healthcare payers struggle to allow their enrollees access to the best medical interventions while simultaneously constraining costs of pharmaceuticals, which are rising at rates far faster than prices in other sectors of the healthcare economy. This report is a brief review of the consequences and costs of NSAID utilization and evaluates published studies that have examined the economic implications of coxib use. In the absence of real-world data on coxibs in the general population, most of the economic information comes from decision analytic models. Although these simulations cannot substitute for actual use studies, they can provide the foundation for making rational decisions regarding the allocation of health resources, until clinical data become available. Clinical Consequences and Costs of Nonsteroidal Anti-inflammatory Drug Use The clinical outcomes positive and negative of NSAID use are discussed in an accompanying article in this supplement. 9 The significance of GI adverse events, however, and their contribution to the cost of treatment merits a brief review. The most serious and costly GI events associated with NSAID use are complications often referred to as PUBs (perforations, ulcers, and bleeding). These events often result in hospitalization or death. Although the annual complication rate for an individual NSAID user is low (an estimated 0.7% in patients with OA and 1.3% in patients with RA), 10 the large number of chronic users in the United States (at least 13 million with musculoskeletal conditions) 11 makes PUBs one of the most important drug-related adverse events. According to recent reviews of the impact S530 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 2002

3 Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care of NSAID-associated gastropathy in the United States, approximately hospitalizations and deaths occur each year, at a cost of more than $2 billion annually. 10,11 Prescription NSAIDs are not solely responsible for adverse effects. NSAIDs sold OTC at lower doses than their prescription counterparts have been demonstrated to significantly increase the risk of upper GI bleeding in patients using them compared with people who do not use NSAIDs. 12 While these lower NSAID doses are safer to the GI tract than higher prescription doses, it is unknown how many people may be taking OTC NSAIDs in addition to their prescription agent. This point is critical, since it is well established that combining 2 NSAIDs including lowdose aspirin significantly increases the risk of GI hemorrhage when compared with either agent alone. Strategies to Decrease NSAID-Related Gastrointestinal Adverse Events Identify Risk Factors. The identification of specific factors that increase the risk of serious GI events has helped clinicians to recognize and manage patients at risk for NSAID-associated gastropathy. The risk factors most often cited include increasing age, concomitant corticosteroid use, prior history of GI events, presence of comorbid conditions, and high dosing or multiple NSAID use. In addition, the use of anticoagulation therapy is a known risk factor, as is low-dose aspirin (for reasons noted above). Cigarettes and/or alcohol are possible exacerbating factors. To prevent these serious complications, measures to reduce the risk of GI hemorrhage should be instituted before symptoms develop in high-risk patients. GI symptoms such as dyspepsia, which may occur in up to half of chronic NSAID users, are not correlated with more serious GI adverse events. However, the importance of symptomatic events such as dyspepsia, abdominal pain, and nausea, which occur commonly to patients at all risk levels, should not be discounted. Symptomatic episodes have an important impact on treatment outcomes and costs. It is well known that healthcare resource utilization (eg, physician visits, diagnostic tests, utilization of GI protective agents) is symptom driven, and an intervention that can influence that rate of symptomatic events can have significant clinical and economic impact Additionally, it is often these nuisance symptoms, especially dyspepsia, that result in reduced quality of life 17 and the discontinuation or switching of drugs, thereby decreasing treatment efficacy Use of Coxibs. Of the management strategies for reducing the NSAID-associated GI events noted in the Table, using a safer but equally effective anti-inflammatory agent would appear to be a desirable option for an individual at risk for NSAIDrelated adverse events. The coxibs were developed in an attempt to provide such an option. Coxibs are a group of drugs that take advantage of the difference in physiologic function of the 2 COX isoenzymes. As discussed earlier in this supplement, COX-1 is responsible primarily for homeostatic functions including gastroprotection, and COX-2 is associated with the inflammatory response and is rapidly induced as a proinflammatory enzyme. 21 In contrast to traditional NSAIDs, whose general inhibition of COX-1 and COX-2 accounts for both efficacy and toxicity, coxibs specifically inhibit COX-2. The targeting of COX- 2 ensures the efficacy of treatment, while the COX-1 sparing provides the improved tolerability and reduction in risk of GI events that have been observed with these drugs (reviewed in this supplement). 9 Coxibs were originally developed as safer alternatives to traditional NSAIDs for chronic conditions such as OA and RA. However, the indications for these drugs are likely to expand. Celecoxib has been shown to be effective in patients with familial adenomatous polyposis 22 and has been approved for this indication; rofecoxib and celecoxib have demonstrated efficacy for peri- and postoperative pain in several surgical interventions ; coxibs are currently being evaluated for treatment of Alzheimer s disease 28 ; and both VOL. 8, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S531

4 REPORTS rofecoxib and celecoxib have recently shown efficacy as adjunctive medication, rofecoxib in combination with rizatriptan 29 for the treatment of migraine and celecoxib for schizophrenia in combination with risperidone. 30 As prescribing by clinicians and use by patients of coxibs expand, the higher acquisition costs of these drugs relative to traditional NSAIDs several of which are available in generic form are likely to have profound consequences for healthcare budgets. The magnitude of the economic impact is suggested by available prescription and cost data. Over a 1-year period, 37 million prescriptions were written for coxibs in the United States. Although this number was 50% less than for traditional NSAID prescriptions, the drug acquisition cost ($2.88 billion) was almost 1.5 times greater than that spent on traditional NSAIDs. 1 It is therefore important to establish the clinical and economic value of these innovative agents in order to make well-informed decisions regarding their use. From a broader perspective, it is critical to look beyond direct cost comparisons of drugs under investigation. Hence, all of the healthcare resources incurred over the entire episode of care for a specified condition should be taken into account. Superiority in GI safety should recover added drug costs in terms of fewer hospitalizations, endoscopies, and GI protective therapies. Moreover, the clinical indications for, and side effects of, chronic anti-inflammatory therapy often necessitate changing NSAIDs, or adding co-therapy for prophylaxis or symptom control. Savings in drug costs diminish (and may be eliminated) as adverse events occur and/or a greater proportion of the patient population eventually switch to the safer regimen. Pharmacoeconomic Analyses Concerns by healthcare payers about escalating expenditures related to new therapeutic interventions have led to increased scrutiny of both the clinical and economic effect of these innovations. While there is little debate that patients, physicians, and payers are interested in services that improve clinical outcomes, providing the best intervention to every eligible individual is not economically feasible. To assist decision makers in their allocation of scarce healthcare resources, the field of pharmacoeconomics provides a methodologically rigorous approach to determining the relative value of available management strategies by taking into consideration both clinical and economic perspectives. With the publication in several countries of guidelines for the economic evaluation of drugs, cost-effectiveness analysis has become almost as important for inclusion on a formulary as the clinical trials documenting efficacy and safety. The increasing importance of pharmacoeconomics is also suggested by the development of guidelines for disease-specific economic evaluations. Guidelines to define clinically relevant variables and end points for inclusion in economic analyses appropriate for specific disease states, such as those currently being discussed for rheumatic diseases by the OMERACT (Outcome Measures in Rheumatology) Economic Working Group, can facilitate economic evaluation and comparison among different strategies and models. 34 Controlled evaluations, often alongside clinical trials, are known to be the most rigorous approach to glean useful economic data. In the absence of these trials, decision analytic models a method that synthesizes the best available data have been used to evaluate and compare strategies for reduction of NSAID-associated GI outcomes. Evaluating Economic Analyses Choosing the Appropriate Comparison. In evaluating economic analyses in general, and modeling studies specifically, a critical aspect is to consider the clinical relevance of the strategies evaluated. For example, a study that evaluates the economic advantages of prophylactic strategies to reduce NSAID-associated gastropathy compared with no prophylaxis may not be germane to a decision maker who is deciding among available prevention S532 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 2002

5 Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care options. 35 When an intervention is compared with no treatment, the intervention frequently demonstrates cost-effectiveness. Unfortunately, this is usually not the costeffectiveness calculation that the decision maker is seeking. It is also important to note that national or regional variations in costs or healthcare systems and resources may impact the applicability of the model under consideration. Appraise the Model and Its Inputs Carefully. The quality of decision analytic modeling studies depends on the model programmed, the assumptions applied, and the data incorporated. It is crucial that the pathways defined by the decision model (the engine ) make clinical sense, and that the data that populate the tree (the inputs ) are obtained from reputable (preferentially published) sources. As an example, a study that suggested the cost-effectiveness of acetaminophen when compared with ibuprofen, coxibs, and ibuprofen plus misoprostol for individuals with OA highlights how input selection can influence the results. 36 In this analysis, the assumptions regarding efficacy were derived from the percentage of patients who achieved minimum perceptible clinical improvement on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index pain subscale. Although minimum perceptible improvement is an objective parameter, how this measurement corresponds with a clinically relevant patient-centered outcome is unclear. This point is especially important considering that in a comparative controlled trial of acetaminophen, rofecoxib, and celecoxib, 31% of the patients in the acetaminophen group withdrew because of the drug s lack of efficacy, in comparison with only 18% to 19% of patients in the coxib groups. 37 Although these withdrawal data are important to consider even when assuming equal efficacy reports indicate that many patients prefer NSAIDs over acetaminophen for symptomatic pain relief in arthritic conditions. 6,38 Make Sure All Relevant Outcomes Are Included. When evaluating an economic analysis, it is imperative to include all relevant clinical and cost outcomes. The importance of measuring the impact of side effects of therapy can be illustrated by the experience with cost-effectiveness analyses of misoprostol, an agent that effectively reduces serious GI adverse events. 39 Misoprostol, however, is associated with adverse events, notably a high incidence of diarrhea that decreases its usefulness, because in clinical practice many patients discontinue the drug due to this side effect. The cost-effectiveness of misoprostol (or any agent), therefore, is sensitive to the rate of patient compliance. When side effects were considered in a cost-utility analysis that quantified the negative consequences of GI adverse events, misoprostol was found to have neutral or negative clinical benefits. 40 Similarly, the mechanism-based, dosedependent cardiorenal effects of NSAIDs and coxibs may also be relevant in future pharmacoeconomic analyses. Economic Analyses of Coxibs With the introduction of celecoxib and rofecoxib, several economic models were developed to evaluate whether the reduction in risk of GI events was worth the higher acquisition costs of these drugs relative to traditional NSAIDs. Although an indepth discussion of the methodology used in these analyses is beyond the scope of this review, the models do conform to the checklist guidelines suggested by Drummond et al 41 for pharmacoeconomic analyses. Two coxib-specific models have been developed, one each for rofecoxib and celecoxib, as well as a third generalized model that compares 2 clinical strategies for the management of patients who require chronic NSAID therapy. Celecoxib Pharmacoeconomic Models. The Arthritis Cost Consequence Evaluation System (ACCES) model, 42 which has been used to compare the economic impact of celecoxib versus other treatments (individual NSAIDs, NSAID basket, and NSAIDs with gastroprotective agents [GPAs]), is a flexible decision analytic model (Figure 1) 42 that can be customized by changing VOL. 8, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S533

6 REPORTS Figure 1. Simplified Decision Tree Used in the Celecoxib Arthritis Cost Consequence Evaluation System (ACCES) Model Loss of efficacy Diarrhea GI discomfort Celecoxib Symptomatic ulcer Treatment Celecoxib Loss of efficacy Diarrhea GI discomfort Symptomatic ulcer Anemia Serious GI event Comparator Anemia Serious GI event Success Success Comparator Comparators include branded and generic nonsteroidal anti-inflammatory drugs (NSAIDs), NSAIDs plus gastroprotective agents (H 2 -receptor antagonists, proton pump inhibitors, and misoprostol), and fixed-dose misoprostol/diclofenac (Arthrotec, G.D. Searle & Co, Chicago, IL). Squares indicate decision nodes (treatment choices); circles, probability nodes derived from clinical trials or observational/epidemiologic studies; triangles terminate the sequence; GI, gastrointestinal. Adapted with permission from Pettitt et al. 42 input variables or comparators to reflect country-, provider-, or perspective-specific objectives. While the risk for NSAIDassociated GI events was obtained from epidemiologic studies, probabilities (risk reduction rates) for celecoxib and comparator treatments were obtained from clinical trials, several of which used the surrogate end point of endoscopic ulcers. These rates can be adjusted for baseline individual or population risk using an algorithm based on the Fries risk scoring system. 43 The model also takes into account the variability of discomfort rates over time, a lack of efficacy outcome, and an adjustment for a secondary event subsequent to a change in therapy. The ACCES model has been used in several country-specific settings to model costs of celecoxib for OA and RA. In Norway and Sweden, celecoxib demonstrated economic dominance (improved outcomes at reduced cost) or favorable cost-effectiveness ratios (comparable with ratios for other accepted interventions) for all primary and sensitivity analyses when compared with NSAID monotherapy or a base case of NSAIDs and NSAIDs plus GPAs. 44,45 The cost-effectiveness of celecoxib was also demonstrated in a Swiss model. 46 The sensitivity analysis suggested that a small differential in acquisition cost between celecoxib and NSAIDs may be responsible for the results that consistently favored celecoxib across all risk categories. In contrast, a Canadian model suggested that whereas NSAID monotherapy provides the lowest cost, followed by celecoxib, the costs of treatment were sensitive to the GI risk of the population, with celecoxib becoming more favorable in patients at increased risk. 47 In all models, celecoxib was associated with significant reductions in GI events and resource utilization. The difference in cost-effectiveness results between the Canadian model and the European models likely reflects differences in drug prices and practice patterns in different healthcare systems. An evaluation S534 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 2002

7 Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care Figure 2. Decision Tree Used in the Rofecoxib Pharmacoeconomic Model Hospitalization Surgery GI symptoms Major GI symptoms Confirmed perforation, ulcer, or bleed Investigated perforation, ulcer, or bleed Outpatient treatment Inpatient investigation Outpatient investigation No surgery Nonselective NSAID Minor GI symptoms Treated Not treated Osteoarthritis patient (paracetamol failure) No GI symptoms Rofecoxib The square indicates decision node (treatment choices); circles, probability nodes derived from clinical trials or observational/epidemiologic studies; triangles terminate the sequence; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug. Reprinted with permission from Marshall et al. 49 of the economic impact of celecoxib in the United States has not yet been published. Rofecoxib Pharmacoeconomic Models. The economic evaluation of rofecoxib also used decision analysis to model the costs and consequences of this drug compared with traditional NSAIDs (a weighted mixture of ibuprofen, diclofenac, and nabumetone) in patients with OA older than 65 years with an average risk of GI events (Figure 2). 48,49 In both the Canadian and the US analyses, significant reductions in GI events were obtained with rofecoxib at what might be considered favorable incremental costs: $Can 2247/PUB averted; $US 4738/PUB averted and $US /life-year gained. These models estimated lower nondrug resource utilization (due to reduced GI complications) that partially offset the higher acquisition cost of rofecoxib. Sensitivity analysis in each model suggested that the outcomes were sensitive to the baseline risk of PUBs; increasing risk led to enhanced cost-effectiveness. Outcomes were also demonstrated to be sensitive to the rate of prescription of GPAs among both NSAID and rofecoxib users; the cost-effectiveness of rofecoxib increased as the rate of GPA utilization increased among NSAID users and as the GPA prescription rate was concomitantly reduced by utilization of rofecoxib (Figure 3). 49 A recent analysis also reported an acceptable incremental cost-effectiveness of rofecoxib in patients older than 65 years with RA. 50 Symptom-Driven Model To quantify the tradeoff between higher drug acquisition prices and savings due to reduced GI adverse events, Fendrick and colleagues 51 constructed a symptom- VOL. 8, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S535

8 REPORTS Figure 3. Sensitivity Analysis Demonstrating the Effect on Treatment Costs of the Relationship Between GPA Prescription in NSAID Users and Reduction in GPA Prescription With Rofecoxib Difference in Annual Cost: Rofecoxib Versus Nonselective NSAID ($Can) % 30% 60% 90% 100% Base Case Rate of GPA Coprescribing in Nonselective NSAID Strategy (%) Cost Rofecoxib > Cost NSAID Cost Rofecoxib < Cost NSAID The lines correspond to percentage reductions in the rate of GPA coprescribing with rofecoxib in the sensitivity analysis. GPA indicates gastroprotective agent; NSAID, nonsteroidal anti-inflammatory drug. Reprinted with permission from Marshall et al. 49 Figure 4. Markov Model Used in a Symptom-Driven Economic Analysis Evaluating the Cost-Effectiveness of a Restrictive Strategy of Coxib Utilization Probability of Developing Symptoms No ulcer No symptoms No ulcer Symptoms present Probability of Developing Ulcer Ulcer complication Symptoms present Ulcer present No symptoms Ulcer present Symptoms present Symptoms and ulcer status were independently modeled because their incidence may be mutually exclusive, but in all cases diagnostic and therapeutic interventions were conducted only when patients presented with symptoms. Reprinted with permission from Fendrick et al. 51 driven Markov simulation that mimicked real-world clinical practice (Figure 4). Specifically, restricted use of a safer, more expensive NSAID (only for those patients experiencing a GI event or for patients intolerant of the generic NSAID) was compared with unrestricted use. Unlike the models reported above, the use of prescription H 2 -receptor antagonists and proton pump inhibitors was included. The fact that the driving force behind the model was the presence of clinical symptoms not endoscopic ulcers provides a more realistic approach to management, because symptoms, whether nuisance side effects or serious GI events, result in the patient healthcare provider interactions that drive treatment costs. Three aspects of this approach differ from models using event probability estimates derived from surrogate end points (such as endoscopic ulcers). First, patients with an endoscopic lesion may be asymptomatic, and thus would neither seek treatment nor incur treatment costs unless the lesion progresses to symptoms or a complication as the first event that may occur in clinical practice. 52 Second, symptoms do not correlate with the presence of ulcers and may be present in the absence of objectively identified lesions The presence of symptoms in the absence of ulceration is a common event that results in costs related to diagnostic testing and the use of GI comedication. Last, because clinical history and physical examination are poor predictors of the presence of ulcers, 20 diagnostic testing is the only method of distinguishing between symptomatic patients with and without lesions. Consequently, the use of empiric therapy in symptomatic patients results in the same treatment for all patients regardless of ulcer status. Again it should be emphasized, as shown in Figure 4, that patients can transition between any of the health states in a nonprogressive manner. Inputs for this model were based on a population at average risk for GI events that was not using low-dose aspirin. The chosen data inputs reflected clinical practice as realistically as possible. The model estimated that for chronic NSAID users at S536 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 2002

9 Cost-Effective Use of NSAIDs: Issues Pertinent to Coxib Use in Managed Care Figure 5. Sensitivity Analysis Demonstrating Dependency of Cost per Ulcer Prevented on Relative Safety of Safer Agent (A) and Relative Ulcer Risk of the Patient or Population (B) Cost Per Ulcer Prevented ($) A Complicated ulcer Symptomatic ulcer Relative Safety of Safer NSAID Compared With Generic NSAID Cost Per Ulcer Prevented ($) B Complicated ulcer Symptomatic ulcer Relative Ulcer Risk Compared to Principal Analysis Reprinted with permission from Fendrick et al. 51 average ulcer risk, the unrestricted use of safer regimens has the potential to decrease ulcer-related adverse events at an incremental cost of $ per complication prevented. 51 The analysis concluded that decisions regarding access to safer, more expensive NSAIDs depend on the cost differential between agents, the relative safety among available regimens, and, most important, the individual patient s ulcer risk. 51 According to the model, the unrestricted use of the safer drug resulted in a 6-fold reduction in the costs of complications (which partially offset the added drug acquisition cost). Despite these cost offsets, the restrictive strategy still resulted (for patients at average risk) in lower total overall costs, which are driven primarily by the cost differential between the drugs. Costs per ulcer prevented decreased as the relative safety of the superior drug improved (Figure 5A). 51 More important, the simulation estimated that the added cost to prevent an NSAID-related complication fell dramatically as the patients risk of an NSAID-related adverse event increased (Figure 5B). Under these conditions, several conclusions can be drawn: 1) The safer but more expensive agent is less cost-effective in patients at low risk (incremental costeffectiveness ratio approaches $ per complicated ulcer avoided); 2) chronic users at moderate risk can be expected to have favorable incremental costs that may be comparable with other accepted gastroprotective therapies (ie, misoprostol); and 3) the lowest incremental costs can be obtained by targeting patients at high risk of events. Thus, for patients at above-average ulcer risk (eg, patients with risk factors such as prior GI hemorrhage, concomitant steroid or anticoagulant therapy), the argument to recommend the routine initial use of coxibs stands on considerable merit. This model is consistent with the other coxib studies 48,49 and another recent study, also using a Markov model, 56 suggesting that cost-effectiveness is related to GI risk. In that study, the incremental cost-effectiveness ratio per quality-adjusted lifeyear gained was evaluated for rofecoxib and celecoxib. Both agents were found to be economically favorable in high-risk and elderly patients, but for average-risk patients coxibs did not appear to be a worthwhile investment in this particular model. The improved cost-effectiveness of coxibs in high-risk patients supports what appears to be current recommended prescribing patterns. Recent data suggest that patients with increased risk of GI events are being switched to or initiated on coxibs. These patients have a greater history of GI adverse drug reactions and higher VOL. 8, NO. 17, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S537

10 REPORTS rates of utilization of GPAs and healthcare resources. 57 Given the nature of the methodology, coxibs could possibly provide greater benefits than indicated by economic modeling. The suggestion that the NSAID-attributable risk is higher in patients without a history of GI events, 58 combined with the observation that rofecoxib reduced the risk of GI events by 88% in a subpopulation of patients having no risk factors, 59 indicates that certain assumptions and probabilities related to risk may need to be reevaluated. Similarly, several assumptions made in the symptom-driven model are also likely to underestimate the clinical and economic effect of coxibs. Nonulcer symptoms (eg, dyspepsia) and efficacy were assumed to be the same in both treatment strategies (ie, restricted versus unrestricted use of a safer, more expensive NSAID). However, rofecoxib and celecoxib have both demonstrated higher rates of compliance (which affects clinical efficacy) and reduced rates of dyspeptic symptoms (which drives resource utilization such as diagnostic testing and use of GPAs). Consistent with these findings are recent reports of reduced health resource utilization associated with the use of rofecoxib Underestimation of benefit is also likely because the model valued only direct medical costs and did not account for indirect costs, an outcome that is increasingly being used as an end point in cost-effectiveness analyses. Although these models provide a useful measure of economic impact, studies based on real-world data in which clinical factors are present that are not included in models (eg, concomitant use of low-dose aspirin, OTC NSAIDs, or other prescribed medications) are needed to confirm or contradict the models and/or their assumptions. Conclusion Although consensus is lacking regarding the best strategy to prevent NSAIDrelated GI complications, assessments of alternative treatment strategies clearly must take into account both clinical effects and economic consequences. Although the various regimens may differ markedly in acquisition cost, the cost-effectiveness of a specific NSAID regimen does not depend entirely on the purchase price of the drug(s) prescribed. The relative value of different approaches also depends on the likelihood of the patients symptomatic response and resultant ulcer and nonulcerrelated healthcare expenditures. No matter the strategy, clinicians must first recognize the presence or absence of clinical risk factors that have been shown to increase the likelihood of GI complications. The best available data suggest that a patient s underlying risk for adverse events, the particular NSAID used, and the use of other medications (eg, aspirin, proton pump inhibitor) determine the clinical and economic attractiveness of available treatment options. Even in the current cost-sensitive environment, first-line use of a coxib or the addition of a proton pump inhibitor to a nonselective NSAID should be offered to individuals at increased risk for NSAID-related GI complications. Both rofecoxib and celecoxib have been found to be cost-effective in several condition-specific models. Support for these assumptions has been demonstrated in outcomes studies that confirm the reduction in GI outcomes and health resource utilization. 69 These findings suggest that a balance needs to be achieved between patient (reduced complications) and payer (healthcare costs) interests. The development of evidence-based strategies that can effectively identify and manage patients at different risk levels is a critical first step.... REFERENCES Retail and Provider Perspective, National Prescription Audit, Plymouth, PA: IMS Health; Infoscan Services, Internal Analgesics Category, Total Food, Drug and Mass Merch, 52 weeks ending July 16, Plymouth, Pa: Information Resources, Inc; Nonprescription Drugs USA 1999, Internal Analgesics Product Category. Little Falls, NJ: Kline & Company, Inc; World Health Organization. Cancer Pain Relief and Palliative Care: Report of a WHO Expert S538 THE AMERICAN JOURNAL OF MANAGED CARE NOVEMBER 2002

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