This report was reviewed for medical and scientific accuracy by Leonard H. Sigal, MD, Professor of Medicine and Pediatrics, Chief, Division of Rheumatology & Connective Tissue Research, University of Medicine and Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Matthew H. Liang, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

New data presented at the 2002 American College of Rheumatology (ACR) 66th Annual Scientific Meeting indicate that initiating treatment of osteoarthritis with acetaminophen (Tylenol) is the most cost-effective strategy when compared to initiating treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2 specific inhibitors.¹ These findings support the current ACR guidelines on the medical management of osteoarthritis that recommend acetaminophen as initial therapy for osteoarthritis based on its overall cost, efficacy, and toxicity profile.²

Utilizing a mathematical simulation, Dr. Lisa Mandl, Dr. David Fisman and I evaluated eight plausible treatment strategies examining the impact of medication order on cost-effectiveness in treating osteoarthritis.¹ The study also evaluated the impact of adjunctive intra-articular corticosteroids on effectiveness and cost. The mathematical model simulated a cohort of 65-year old patients with newly diagnosed osteoarthritis of the knee. Quality of life assessments were taken from published data which reflected a utility range from perfect health (1.0) to death (0). The mathematical model then estimated quality-adjusted life expectancy values by estimating the utility of each health state (0-1) and the time spent in each state. The comparative cost-effectiveness of each treatment strategy was expressed using the incremental cost-effectiveness ratio (or the additional cost per quality-adjusted life year gained compared with the next best competing strategy).

After adjusting for probabilities in intolerance and risk of bleeding, the most cost effective treatment strategy consisted of starting with acetaminophen, followed by the NSAID naproxen (Naprosyn) plus misoprostol (Cytotec), and followed by a COX-2 specific inhibitor, celecoxib (Celebrex) or rofecoxib (Vioxx). Interestingly, initial treatment with intra-articular corticosteroids produced even further improvements in cost-effectiveness. This suggests that perhaps further evaluation of intra-articular corticosteroids in this context is warranted.

In a related study, Fraenkel and colleagues reported the results on providing alternative treatment options to older patients with osteoarthritis and the resulting impact on patient preferences.³ Numerous studies have shown that the vast majority of patients want to be informed of all available treatment options when faced with medical decisions. The objective of the study was to examine whether the current widespread use of NSAIDs and COX-2 specific inhibitors actually reflects patients' preference after a presentation of the therapeutic choices. Investigators found that when patients were offered a third treatment option that may be considered less effective but a safer alternative (eg, acetaminophen, capsaicin or glucosamine) that their preference was strongly influenced toward the third treatment option.

Both findings have significant implications for the management of osteoarthritis. Presently, over 21 million Americans have osteoarthritis. With the "aging" of the baby boomers, it is expected that osteoarthritis will be even more prevalent. From an economic perspective, cost of treating osteoarthritis, its complications and the resulting disability has been estimated at $65 billion.⁴ Given that osteoarthritis is a chronic disease with no cure and requires life-long management, it is critically important that one take a stepped approach.

The need for safe, efficacious and cost-effective treatment strategies is clear. The results of these studies, one supporting the use of acetaminophen as the initial pharmacologic treatment in osteoarthritis, the other advocating more informed patient education on the availability of alternative treatments to NSAIDs and COX-2 specific inhibitors, will go a long way in addressing that need.

A Cost-Effectiveness Analysis in Treating Osteoarthritis

Lisa A. Mandl, MD, MPH, and Matthew H. Liang, MD, MPH from the Division of Rheumatology, Immunology and Allergy, Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts and David N. Fisman, MD, MPH, from the Department of Public Health, Hamilton, Ontario, Canada studied the cost-effectiveness of several pharmacologic treatment regimens for osteoarthritis,¹ based on ACR guidelines on osteoarthritis.² Specifically, investigators evaluated the impact of medication order on cost-effectiveness and the impact of adjunctive intra-articular steroids on clinical effectiveness and cost.

The investigators used a Markov model to simulate the initial management, clinical course, downstream complications, and costs associated with eight treatment strategies. A Markov model simulates life as a series of mutually exclusive health states. In the model, patients cycle through various health states over time until they all reach the "dead" state. Six-week cycles were chosen to reflect the time frame for trials of therapy.

The Markov model was used to simulate a cohort of 65-year old patients with newly diagnosed osteoarthritis of the knee. Treatments consisted of eight plausible pharmacologic strategies with the patient moving through a sequence of 4 possible medications (Table 1). Each strategy incorporated a combination of acetaminophen 1000 mg four times a day, naproxen 375 mg twice a day, naproxen 375 mg twice day plus misoprostol 200 mg four times a day, celecoxib 200 mg twice a day or rofecoxib 25 mg once daily. All treatment strategies were compared to one another and to a non-treatment strategy, in which individuals lived a normal lifespan but with impaired health-related quality of life. The parameters of the study allowed patients to switch medications due to intolerance, adverse events or lack of efficacy; however, they could not go back on a medication once it had failed. Once a particular treatment strategy was exhausted, the patient would go on to have a total knee replacement.

The investigators used the model to estimate average lifetime costs and quality-adjusted life expectancy for each treatment strategy. Quality of life assessments were conducted using data from published analyses which reflected a utility range from perfect health (1.0) to death (0). The mathematical model then estimated quality-adjusted life expectancy values by estimating the utility of each health state (0-1) and the time spent in each state. Quality-adjusted life expectancy values represent an individual's preference for a different health state. The comparative cost-effectiveness of each treatment strategy was expressed using the incremental cost-effectiveness ratio which indicated the additional cost per quality-adjusted life year gained compared with the next best competing strategy. In other words, incremental cost-effectiveness addresses the question of most relevance to clinician and patient alike, is the additional cost of one treatment strategy, compared to the cost of another, for a given level of desired expenditure, worthwhile in treating osteoarthritis? By using this standard measure, the cost-effectiveness of alternative treatments may be compared and utilized to adopt to the most efficient treatment options.

Data on medication efficacy, tolerance, and complications were taken from published medical literature, preferentially using data from long-term randomized controlled clinical trials. The probability of discontinuing therapy due to lack of efficacy or adverse events (eg, intolerance, risk of bleeding or infection) was taken from published medical literature, with preference given to randomized clinical trials. Treatment costs were based on 2000 "Red Book" wholesale prices,⁵ and costs of procedures and hospitalizations were based on average Current Procedural Terminology (CPT) and Medicare reimbursement rates. All costs and benefits were discounted at a 3% annual rate. Utilities were based on published time-trade-off preferences of patients with arthritis. (For example, in this study, untreated knee osteoarthritis had a utility value of 0.66, whereas a knee responsive to treatment had a utility value of 0.84. A total knee replacement carried a value of 0.72.)

Strategy with First-Line Acetaminophen Most Cost-Effective

Overall, the most cost-effective treatment strategy was #3 (Table 1), with an incremental C/E ratio of $19,610 per quality-adjusted life year. In other words, when this treatment strategy is compared to no treatment ($0 cost, quality-adjusted life expectancy value of 8.57), it produces the most efficient treatment option [the incremental cost-effectiveness ratio is an inverse relationship—the lower the numerical value—the greater the effectiveness]. This strategy initiated treatment with acetaminophen, followed by naproxen, followed by naproxen plus misoprostol and finally a COX-2 specific inhibitor. According to Dr. Mandl, this incremental C/E ratio compared favorably with that of most widely accepted medical interventions for osteoarthritis. Adding intra-articular corticosteroids to this strategy (#3) was even more cost effective resulting in an incremental cost-effectiveness ratio of $19,100.

This cost effectiveness analysis validates the ACR recommendations that acetaminophen should be the initial therapy for treatment of osteoarthritis.

Additional Information Influences Patient Preferences for Treatment

Numerous studies have shown that the vast majority of patients want to be informed of all available treatment options when faced with medical decisions. In order to determine whether the current widespread use of NSAIDs and COX-2 specific inhibitors actually reflected a lack of informed choice versus preference for a particular treatment, investigators interviewed 100 patients with osteoarthritis after completion of an adaptive conjoint analysis questionnaire.³ Preferences were calculated based on individual patient trade-offs involving medication characteristics (response rate, time to benefit, risk of gastrointestinal toxicity) and monthly out-of-pocket costs.

On initial assessment, 55% of patients interviewed preferred COX-2 specific inhibitors over NSAIDs. When investigators suggested a third treatment option to the patients (acetaminophen, capsaicin, or glucosamine), that might be considered less effective but safer (no gastrointestinal toxicity), 100% of the patients preferred trying the alternative treatment option. When patients were offered a treatment option that might be considered less effective, with no gastrointestinal toxicity, delayed onset of action, and taken four times a day, patient preference for that option dropped to 76.3%. When cost was added to the parameters, patient preference for the alternative treatment dropped to 60.0%.

Investigators concluded that adding a third treatment option for patients with osteoarthritis patients strongly influenced their preference for NSAIDs and COX-2 specific inhibitors. Moreover, the widespread use of both NSAIDs and COX-2 specific inhibitors may reflect lack of informed choice among older patients.

Conclusion

New data presented at the 2002 ACR 66th Annual Scientific Meeting indicate that initiating treatment of osteoarthritis with acetaminophen is the most cost-effective strategy when compared to initiating treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2 specific inhibitors. These findings support the current ACR guidelines for the medical management of osteoarthritis that recommend acetaminophen as initial therapy for osteoarthritis based on its overall cost, efficacy, and toxicity profile. Moreover, when offered to osteoarthritis patients as a possible treatment alternative to NSAIDs and COX-2 specific inhibitors (in addition to glucosamine and capsaicin), patient preference for these agents dropped dramatically; perhaps, reflective of a lack of informed choice. These results underscore the importance of patient education as an integral part of the decision-making process.

References

1. Mandl LA, Liang MH, Fisman DN. Cost-Effectiveness of Competing Strategies for Management of Knee Osteoarthritis. Presented at the American College of Rheumatology 66th Annual Scientific Meeting, October 25-29, 2002, New Orleans, Louisiana. Presentation 1564.
2. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-1915.
3. Fraenkel L, Fried T, Concato J, Wittink D. Patients prefer anti-inflammatory drugs... if they are unaware of other choices. Presented at the American College of Rheumatology 66th Annual Scientific Meeting, October 25-29, 2002, New Orleans, Louisiana. Presentation 993.
4. Yelin E. The Economics of Osteoarthritis. In Brandt KD, Doherty M, Lohmander LS, eds. Osteoarthritis. New York: Oxford University Press. 1998.
5. 2000 Drug Topics Red Book. Medical Economics Company, Inc., Montvale, NJ.

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Disclosure
Matthew H. Liang, MD, MPH
Research Support-McNeil Consumer and Specialty Pharmaceuticals; Consultant-Pfizer

Leonard H. Sigal, MD
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Rheumatology Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Rheumatology Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education