1 Department of Medicine, Division of Rheumatology, Immunology and Allergy, Harvard Medical School, Robert B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases Center, Brigham and Women's Hospital, Boston, Massachusetts, USA,
2 Department of Internal Medicine, Division of Rheumatology, Hanyang University College of Medicine, the Hospital for Rheumatic Diseases, Seoul, Korea,
3 2nd Department of Internal Medicine, Christian Albrechts University, Kiel, Germany and
4 Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, USA
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Abstract |
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Methods. Markov (state transition) models were used to simulate a cohort of RA patients taking disease-modifying antirheumatic drugs and either corticosteroids or NSAIDs. The regimens were assumed to be equally effective for the control of RA. Data on incidence, costs and consequences of adverse events from corticosteroids and from NSAIDs were taken from the literature. Costs were measured in 1999 US dollars; health effects expressed as quality-adjusted life years (QALYs). Sensitivity analyses were performed including best-case scenarios (0.5x adverse event rate) and worst-case scenarios (1.5x adverse event rate).
Results. In the base-case analysis corticosteroids were superior to NSAIDs. The sensitivity analyses of adverse event rate, using best-case and worst-case scenarios, and age showed that the results were sensitive to each combination of adverse event rate and age. In contrast, the sensitivity analyses of costs and utilities were robust. Using misoprostol or omeprazole prophylaxis with NSAIDs would make corticosteroids cost-effective. Compared with NSAIDs with COX-2 specific inhibition, corticosteroids were still cost-effective.
Conclusion. Corticosteroids are more cost-effective than NSAIDs and COX-2 inhibitors in the long-term treatment of RA.
KEY WORDS: Low dose corticosteroid, Non-steroidal anti-inflammatory drug (NSAID), COX-2 inhibitor, Cost-effectiveness, Inflammatory arthritis, Rheumatoid arthritis.
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Introduction |
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The medical treatment for RA includes non-steroidal anti-inflammatory drugs (NSAIDs), low dose corticosteroids of <10 mg of prednisone or equivalent, and disease-modifying anti-rheumatic drugs (DMARDs). DMARDs are now being used earlier and earlier in the course of RA and there is evidence that this may be more effective in preventing joint destruction. NSAIDs and corticosteroids, however, are still often needed to control symptoms.
Although higher doses of corticosteroids have a host of documented problems, such as osteoporosis, diabetes, cataract, glaucoma, central obesity, skin thinning and increased susceptibility to infection, adverse events from low doses of corticosteroids are less frequent and less severe than those of higher doses [1, 2]. Indeed corticosteroids may be more effective than NSAIDs [37], possibly have disease-modifying effects [810] in the treatment of RA and are considerably less expensive [3, 11]. Corticosteroids, interestingly, are also a potent COX-2 specific inhibitor [12].
Though not appropriate as monotherapy, RA patients are frequently treated with numerous NSAIDs over their lifetime. Even if synovitis is well controlled, almost all patients are on some dose of a NSAID to control symptoms over the lifetime of disease. However, NSAIDs cannot be used without a potential price and current NSAIDs have a host of side-effects including dyspepsia, NSAID-induced gastropathy (sometimes resulting in hospitalization or rarely in death), renal insufficiency, hepatic toxicity, allergic rashes and cognitive disturbance. New NSAIDs with highly selective cyclo-oxgenase-2 (COX-2) inhibition afford some protection against gastropathy, but their acute and long-term effects on the kidney and central nervous system are unclear and they are relatively expensive compared with conventional NSAIDs [1316]. Celecoxib and rofecoxib are the two COX-2 specific inhibitors currently available and more are anticipated. Celecoxib has been approved for the treatment of RA, while rofecoxib has not yet been approved.
Given that some NSAID usage is inevitable, we posit that corticosteroids might be more cost-effective and safer than NSAIDs or COX-2 specific inhibitors for the chronic treatment of RA.
Since RA is a lifelong, chronic, disabling disease that at present cannot be cured, it is very important to evaluate long-term consequences and economic impact in the assessment of any therapeutic modality. Long-term follow-up studies of either corticosteroids or NSAIDs/COX-2 inhibitors for the treatment of RA are not available and long-term controlled study of the issue would be technically prohibitive and arguably unethical. Even a cursory review of the available literature indicates that long- and short-term adverse events associated with NSAIDs are documented, but the same information on corticosteroids is scant. The latter situation can be approached by formal decision analysis where estimates can be varied by a sensitivity analysis to assess the robustness of the conclusions and where critical data need be collected. Therefore we assessed costs and health effects of corticosteroids compared with NSAIDs/COX-2 inhibitors using a decision-analytic model.
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Methods |
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We compared two treatment strategies to assess costs and health effects of corticosteroids compared with NSAIDs: (1) treat patients with any DMARDs (antimalarial, sulphasalazine, D-penicillamine, methotrexate, gold compound, azathioprine, leflunomide) and corticosteroids; and (2) treat patients with any DMARDs and NSAIDs. Even though recent novel agents such as etanercept and infliximab have been approved for the treatment of RA and data suggest that they retard structural damage, they were not considered in our study since their long-term benefits and adverse effect profile are not known. We assumed both strategies were equally effective for the control of RA since there are no data directly comparing long-term corticosteroids with NSAIDs or COX-2 inhibitors and estimated the response rate at 60% [17]. We assumed that all patients were placed on at least 1 g/day of calcium and 400 IU/day of vitamin D. We did not model the combination of NSAIDs and corticosteroids, reasoning that even though this may be done in practice there are no data to support that this regimen is more efficacious than either alone or that it is less toxic than either alone.
The outcomes (Markov states) examined included corticosteroid complications (hip or other fracture, permanent nursing home care after fracture, diabetes mellitus, cataract, glaucoma, infection), NSAID complications (dyspepsia; gastrointestinal complications such as ulcer or erosion, causing bleeding, perforation, or gastric outlet obstruction; acute hepatic failure; acute renal failure) and death.
Patients recovering from a fracture were considered to be in a post-fracture state and to be candidates for osteoporosis treatment such as oestrogen, calcitonin, etidronate or alendronate. Patients who did not recover from disability after fracture were assumed to require permanent nursing home care. Recurrent fractures in nursing home patients were not specifically accounted for, but assumed to be included in the general estimate of costs and outcomes for nursing home patients. Since the risk of gastrointestinal (GI) complications increases after a GI complication, patients were considered to be in a post-GI complication state. Fracture states, diabetes mellitus, cataract, glaucoma, infection, dyspepsia, GI complication, acute hepatic failure and acute renal failure were considered as temporary states. Patients moved among states based on transition probabilities derived from the literature.
We assumed that corticosteroids or NSAIDs would be discontinued whenever an adverse event occurred and restarted the next year. These adverse events were considered as transient states. Substitute treatments such as paracetamol or cross-over of treatment from NSAIDs to corticosteroids or vice versa would not be considered after the adverse event occurred, but DMARDs would be continued. In practice, patients with RA respond differently to different DMARDs and the disease can flare on these agents even when reasonably controlled. Thus we assumed that any DMARD could be used and changed when RA flared. Medication compliance was assumed to be 100%.
Model data estimates
The estimates for the model were based on a detailed review of the medical literature using Medline (19661999) and the key words corticosteroid, prednisone, prednisolone, glucocorticoid, steroid, NSAID, COX-2 inhibitor, rheumatoid arthritis' and the bibliographies from these papers for additional relevant papers. Data estimates were derived from studies of populations similar to the cohorts simulated in our models. No attempt was made to combine data from multiple studies. We adjusted the mortality rate from published standardized mortality data in RA [18].
The probabilities of adverse events were estimated from published studies (Table 1). The annual probabilities of adverse events caused by corticosteroids were assumed to be increased by 1% per year until death.
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Sensitivity analysis
In a sensitivity analysis, some critical component in the calculation is changed by a meaningful amount or varied from worst case to best case, and the cost-effectiveness ratio is recalculated. The resulting difference in the ratio provides some indication of how sensitive the results might be to a substantial but not implausible change in that parameter. If the major results are insensitive to a reasonable variation in a parameter, then the analyst can be relatively sure that the conclusions are insensitive or robust to the working assumptions about that parameter. If the major results are sensitive to a range of plausible values of a parameter, then the conclusions are not robust [22].
In this analysis, the adverse event rate was the main focus since we assumed the equal efficacy of both treatment strategies. There were very limited data on the adverse event rates of corticosteroids. Therefore, for the sensitivity analysis of adverse event rate, we varied the base case estimate by multiplying with: (1) 0.5 and 1.5x adverse event rate of corticosteroids, and (2) 0.5 and 1.5x adverse event rate of NSAIDs and compared combinations of their probabilities.
We did sensitivity analyses varying age (range, 2060 yr) since the age of our hypothetical cohort was 50 yr. We performed extensive sensitivity analyses to examine the effects of varying cost and utility estimates. In addition, we performed sensitivity analysis using discount factors between 0 and 7%.
Analysis with co-treatments to prevent GI toxicity
Co-treatments such as misoprostol and proton pump inhibitor (omeprazole) prophylaxis were analysed; the annual cost and GI complication rate of misoprostol prophylaxis (400 µg/day) were $656 [20] and 0.0118 [23, 24] and those of omeprazole prophylaxis (20 mg/day) were $1232 [20] and 0.0053 [25], respectively. The GI complication rate of omeprazole prophylaxis was based on published endoscopic data [25].
Analysis with COX-2 specific inhibitors
Recently available COX-2 specific inhibitors such as celecoxib and rofecoxib were analysed. We assumed both COX-2 inhibitors were equally effective and had the same GI complication rate although rofecoxib has not been approved for the treatment of RA and there were no data comparing both COX-2 inhibitors. The annual cost of celecoxib (400 mg/day) or rofecoxib (50 mg/day) was $1767 [20] and annual GI complication rate was 0.002 from a meta-analysis [26]. We performed sensitivity analysis varying cost.
All analyses were performed from the societal perspective and using Decision Analysis Software by TreeAge Software (3.5), Inc. [27].
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Results |
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Sensitivity analysis
Table 4 illustrates the results of sensitivity analyses of adverse event rates using 0.5 and 1.5 times the base case estimate in each strategy. Compared with NSAIDs with 0.5 times the rate of adverse event, corticosteroids were still less costly and more effective than NSAIDs. When we increased the base case adverse event rates of corticosteroids by 1.5, corticosteroids were more costly (incremental cost of $5900) and effective (additional 0.06 QALYs per person) than NSAIDs, yielding an incremental cost-effectiveness (C/E) ratio of 107 706 ($/QALY). When we increased the base case adverse event rates of corticosteroids by 1.5 and decreased the base case adverse event rates of NSAIDs by 0.5, corticosteroids were more costly and less effective than NSAIDs. In contrast to base case analysis, NSAIDs were superior to corticosteroids (Table 4
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When we assumed our cohort was younger than 50 yr of age (base case assumption), corticosteroids were associated with higher costs and better health outcomes than NSAIDs (Table 5). The incremental C/E ratios were between 10 621 and 44 322 ($/QALY).
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Analysis with co-treatments to prevent GI toxicity
When misoprostol prophylaxis was used with NSAIDs, it was more costly ($56 000) and less effective (11.62 QALYs) than corticosteroids; corticosteroids were superior to NSAIDs. If omeprazole was given with NSAIDs, it was more costly and yielded a better health outcome than corticosteroids; its cost and health outcome were $68 000 and 11.77 QALYs. The incremental C/E ratio was 231 895 $/QALY.
Analysis with COX-2 specific inhibitors
In the case of COX-2 specific inhibitors, they were associated with higher cost ($63 000) and better health outcomes (11.81 QALYs). The incremental C/E ratio between COX-2 inhibitors and corticosteroids was 132 880 ($/QALY). The sensitivity analysis varying cost showed that COX-2 inhibitors were superior to corticosteroids when the cost was less than $707 (Fig. 1).
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Discussion |
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Although there is controversy in the use of corticosteroids for the treatment of RA, two meta-analyses [6, 7] suggest that corticosteroids are more effective than NSAIDs. Very few studies have assessed the effectiveness of corticosteroids for RA treatment directly, many are of poor methodological quality, studies directly comparing corticosteroids with NSAIDs are rare, and most of the studies are short term (714 days) [6, 7]. There is only one prospective study longer than 2 weeks which compared prednisone with aspirin over 2 yr and concluded that prednisone was superior to aspirin [28]. However, the average daily dose of prednisone was over 10 mg, which would not be considered low dose by most clinicians. In addition, there was incomplete follow-up and subjects were not consistently maintained in a treatment group over the 2 yr. To date there has been no convincing evidence regarding the direct comparison of the long-term effectiveness of corticosteroids with NSAIDs. We have assumed equal efficacy in both the corticosteroid and NSAID strategies to bias the analysis against corticosteroids, which is not the dominant clinical approach. However, the clinical experience and data support that corticosteroids have an immediate and almost certainly superior benefit in joint symptoms and well-being in the short and medium term [810]. This translates to an improved functioning. It may also have a long-term benefit such as slowing of structural damage. NSAIDs are thought to have a continuing beneficial effect on symptoms for the duration of treatment, but not to change the underlying pattern of joint destruction. Thus if corticosteroid superiority were assumed, the results would be even more favourable for corticosteroid treatment and could be concluded more convincingly.
There is a paucity of data regarding toxicities associated with the long-term use of low dose corticosteroids. We used two published, retrospective, matched cohort studies for adverse event rates of corticosteroids [29, 30]. Even though matched cohort studies did not give adverse event rates directly, we computed adverse event rates by extrapolating the adverse event number of patients with or without corticosteroids. Since these estimates might not reflect real adverse event rates, we performed sensitivity analyses of adverse event rates using worst- and best-case scenarios. Their results were sensitive according to varying adverse event rates. In these studies, however, the patients with corticosteroids were clinically sicker than those without corticosteroids, i.e. higher erythrocyte sedimentation rate, higher percentage of rheumatoid factor and extra-articular manifestation, and more use of DMARDs. One prospective cohort study published only as abstract [31, 32] showed lower incidence rates of hip fracture and cataract compared with our estimates. We included infection as a complication of corticosteroids in the base case analysis although a meta-analysis showed that the infection rate was not increased in patients given a daily dose of <10 mg of prednisolone [33]. Thus our adverse event rates might be overestimates.
The adverse event rates for NSAIDs are based on one trial, MUCOSA (Misoprostol Ulcer Complications Outcome Safety Assessment), a large, double-blind, placebo-controlled, multi-centre trial [23]. The mean age of subjects in the MUCOSA trial was 68 yr, which was higher than our hypothetical cohort, and 43% of patients had used corticosteroids. The GI complication estimate in our analysis, however, was conservatively based on definite GI events excluding probable GI events.
In the base case analysis, a cohort of RA patients aged 50 yr was selected: sensitivity analyses using different age cohorts showed that in younger patients corticosteroids were more costly and more effective than NSAIDs. However, the incremental C/E ratios were less than 50 000 ($/QALY).
COX-2 specific inhibitors such as celecoxib or rofecoxib may have the same effect as conventional NSAIDs in terms of anti-inflammation and analgesia and less endoscopic GI damage. This latter observation also appears to correspond to less clinically significant GI events. The incidence rate of GI complication from COX-2 inhibitors was based on a meta-analysis in abstract form [26], which was one tenth of COX-2 non-specific inhibitors. The incremental C/E ratio between COX-2 specific inhibitors and corticosteroids was about 133 000 ($/QALY), which is considered unacceptable from a societal point of view. The sensitivity analyses varying cost showed that COX-2 inhibitors would be more cost-effective than corticosteroids if their cost were comparable with conventional NSAIDs.
Limitations of the present study
First, we did not model all potential strategies for dealing with adverse events; for instance, when adverse events occurred, substitute treatments were not considered. The substitute treatments reflect a real practice, but their decision tree is complicated and so it is difficult to assess the cost and outcome of each strategy.
Second, some complications, such as skin complications, hypertension, atherosclerosis and cognitive dysfunction, were not modelled because of uncertainty and no or few data [1, 34, 35]. There are no published data of corticosteroid skin complications such as acne, hirsutism, purpura, skin atrophy, spontaneous skin tearing and delayed wound healing in the doses of corticosteroids considered in this analysis. NSAIDs also cause skin complications such as allergic reaction. Higher dose corticosteroids are known to promote atherogenesis, but the effects of low dose corticosteroids are not known. COX-2 inhibitors may also cause cardiovascular events [35]. Long-term treatment with both corticosteroids and NSAIDs may elevate systolic and diastolic pressure [1, 35].
Third, we assumed that each disease status reduced one's utility by the same percentage for RA patients with or without other concomitant complications since all of the combined utilities were not available, and the utilities of concomitant disease were not derived from RA patients. Sensitivity analyses of utility, however, did not change our base case result.
Fourth, the estimates of the cost of fracture were derived largely from simulations.
In conclusion, based on current best data, our study shows that low dose corticosteroids are a better option and more cost-effective whenever NSAIDs or COX-2 inhibitors are needed in the treatment of patients with RA. There are other inflammatory arthritides that need NSAIDs or COX-2 inhibitors. A low dose corticosteroid strategy might also be favoured in the treatment of other inflammatory arthritides where NSAIDs are used and be cost-effective. Finally, decision analysis can point to critical research areas and based on this, additional research on adverse events of low dose corticosteroids would be a high priority.
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Acknowledgments |
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Notes |
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References |
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