Does gabapentin provide benefit for patients with knee OA? A benefit-harm and cost-effectiveness analysis.

OBJECTIVE: Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care. METHOD: We used the Osteoarthritis Policy Model, a validated Monte Carlo simulation of knee OA, to examine the value of gabapentin in treating knee OA by comparing three strategies: 1) usual care, gabapentin sparing (UC-GS); 2) targeted gabapentin (TG), which provides gabapentin plus usual care for those who screen positive for nociplastic pain on the modified PainDETECT questionnaire (mPD-Q) and usual care only for those who screen negative; and 3) universal gabapentin plus usual care (UG). Outcomes included cumulative quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. We derived model inputs from published literature and national databases and varied key input parameters in sensitivity analyses. RESULTS: UC-GS dominated both gabapentin-containing strategies, as it led to lower costs and more QALYs. TG resulted in a cost increase of $689 and a cumulative QALY reduction of 0.012 QALYs. UG resulted in a further $1,868 cost increase and 0.036 QALY decrease. The results were robust to plausible changes in input parameters. The lowest TG strategy ICER of $53,000/QALY was reported when mPD-Q specificity was increased to 100% and AE rate was reduced to 0%. CONCLUSION: Incorporating gabapentin into care for patients with knee OA does not appear to offer good value.

Cost-effectiveness of health coaching and financial incentives to promote physical activity after total knee replacement.

OBJECTIVE: We evaluated the cost-effectiveness of Telephonic Health Coaching and Financial Incentives (THC + FI) to promote physical activity in total knee replacement recipients. DESIGN: We used the Osteoarthritis Policy Model, a computer simulation of knee osteoarthritis, to evaluate the cost-effectiveness of THC + FI compared to usual care. We derived transition probabilities, utilities, and costs from trial data. We conducted lifetime analyses from the healthcare perspective and discounted all cost-effectiveness outcomes by 3% annually. The primary outcome was the Incremental Cost-Effectiveness Ratio (ICER), defined as the ratio of the differences in costs and Quality-Adjusted Life Years (QALYs) between strategies. We considered ICERs <$100,000/QALY to be cost-effective. We conducted one-way sensitivity analyses that varied parameters across their 95% confidence intervals (CI) and limited the efficacy of THC + FI to 1 year or to 9 months. We also conducted a probabilistic sensitivity analysis (PSA), simultaneously varying cost, utilities, and transition probabilities. RESULTS: THC + FI had an ICER of $57,200/QALY in the base case and an ICER below $100,000/QALY in most deterministic sensitivity analyses. THC + FI cost-effectiveness depended on assumptions about long-term efficacy; when efficacy was limited to 1 year or to 9 months, the ICER was $93,300/QALY or $121,800/QALY, respectively. In the PSA, THC + FI had an ICER below $100,000/QALY in 70% of iterations. CONCLUSIONS: Based on currently available information, THC + FI might be a cost-effective alternative to usual care. However, the uncertainty surrounding this choice is considerable, and further research to reduce this uncertainty may be economically justified.

Cost-effectiveness of generic celecoxib in knee osteoarthritis for average-risk patients: a model-based evaluation.

OBJECTIVE: The cost-effectiveness of the recently-introduced generic celecoxib in knee OA has not been examined. METHOD: We used the Osteoarthritis Policy (OAPol) Model, a validated computer simulation of knee OA, to evaluate long-term clinical outcomes, costs, and cost-effectiveness of generic celecoxib in persons with knee OA. We examined eight treatment strategies consisting of generic celecoxib, over-the-counter (OTC) naproxen, or prescription naproxen, with or without prescription or OTC proton-pump-inhibitors (PPIs) to reduce gastrointestinal (GI) toxicity. In the base case, we assumed that annual cost was $130 for OTC naproxen, $360 for prescription naproxen, and $880 for generic celecoxib. We considered a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) and discounted costs and benefits at 3% annually. In sensitivity analyses we varied celecoxib toxicity, discontinuation, cost, and pain level. RESULTS: In the base case analysis of the high pain cohort (WOMAC 50), celecoxib had an incremental cost-effectiveness ratio (ICER) of $284,630/QALY compared with OTC naproxen. Only under highly favorable cost, toxicity, and discontinuation assumptions (e.g., annual cost below $360, combined with a reduction in the cardiovascular (CV) event rates below baseline values) was celecoxib likely to be cost-effective. Celecoxib might also be cost-effective at an annual cost of $600 if CV toxicity were eliminated completely. In subjects with moderate pain (WOMAC 30), at the base case CV event rate of 0.2%, generic celecoxib was only cost-effective at the lowest plausible cost ($190). CONCLUSION: In knee OA patients with no comorbidities, generic celecoxib is not cost-effective at its current price.

Model-based evaluation of cost-effectiveness of nerve growth factor inhibitors in knee osteoarthritis: impact of drug cost, toxicity, and means of administration.

OBJECTIVE: Studies suggest nerve growth factor inhibitors (NGFi) relieve pain but may accelerate disease progression in some patients with osteoarthritis (OA). We sought cost and toxicity thresholds that would make NGFi a cost-effective treatment for moderate-to-severe knee OA. DESIGN: We used the Osteoarthritis Policy (OAPol) model to estimate the cost-effectiveness of NGFi compared to standard of care (SOC) in OA, using Tanezumab as an example. Efficacy and rates of accelerated OA progression were based on published studies. We varied the price/dose from $200 to $1000. We considered self-administered subcutaneous (SC) injections (no administration cost) vs provider-administered intravenous (IV) infusion ($69-$433/dose). Strategies were defined as cost-effective if their incremental cost-effectiveness ratio (ICER) was less than $100,000/quality-adjusted life year (QALY). In sensitivity analyses we varied efficacy, toxicity, and costs. RESULTS: SOC in patients with high levels of pain led to an average discounted quality-adjusted life expectancy of 11.15 QALYs, a lifetime risk of total knee replacement surgery (TKR) of 74%, and cumulative discounted direct medical costs of $148,700. Adding Tanezumab increased QALYs to 11.42, reduced primary TKR utilization to 63%, and increased costs to between $155,400 and $199,500. In the base-case analysis, Tanezumab at $600/dose was cost-effective when delivered outside of a hospital. At $1000/dose, Tanezumab was not cost-effective in all but the most optimistic scenario. Only at rates of accelerated OA progression of 10% or more (10-fold higher than reported values) did Tanezumab decrease QALYs and fail to represent a viable option. CONCLUSIONS: At $100,000/QALY, Tanezumab would be cost effective if priced ≤$400/dose in all settings except IV hospital delivery.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Disease-modifying drugs for knee osteoarthritis: can they be cost-effective?

OBJECTIVE: Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment. DESIGN: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization. RESULTS: Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%. CONCLUSIONS: Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.

Surveillance for isocyanate asthma: a model based cost effectiveness analysis.

AIMS: Because logistical and financial obstacles impede using large prospective cohort studies, surveillance decisions in occupational settings must often be made without evidence of relative benefits and costs. Using the example of isocyanate induced asthma, the most commonly reported immune mediated occupational asthma, the authors developed a model based approach to evaluate the costs and benefits of surveillance from both an employer and a societal perspective. METHODS: The authors used a mathematical simulation model of isocyanate asthma to compare annual surveillance to passive case finding. Outcome measures included symptom free days (SFD), quality adjusted life years (QALY), direct costs, productivity losses, and incremental cost effectiveness ratio (CER), measured from the employer and the societal perspectives. Input data were obtained from a variety of published sources. RESULTS: For 100,000 exposed workers, surveillance resulted in 683 fewer cases of disability over 10 years. Surveillance conferred benefits at an incremental cost of 24,000 dollars/QALY (employer perspective; 13.33 dollars/SFD) and was cost saving from the societal perspective. Results were sensitive to assumptions about sensitisation rate, removal rates, and time to diagnosis, but not to assumptions about therapy costs and disability rates. CONCLUSIONS: Baseline results placed the CER for surveillance for isocyanate asthma within the acceptable range. Costs from the societal and employer perspective differed substantially with a more attractive CER from the societal perspective, suggesting opportunities for employer/societal cost sharing. The analysis demonstrates the value of a model based approach to evaluate the cost effectiveness of surveillance programmes for isocyanate asthma, and to inform shared decision making among clinicians, patients, employers, and society. Such a modeling approach may be applicable to surveillance programmes for other work related conditions.

Cost-effectiveness of cancer screening in end-stage renal disease.

BACKGROUND: Limited evidence suggests that persons with end-stage renal disease (ESRD) may be at increased risk for malignancy. The appropriateness of screening procedures in this population has not been evaluated. OBJECTIVE: To determine the relative cost-effectiveness of hypothetical cancer screening programs in the population with ESRD compared with the general population. METHODS: We performed a cost-effectiveness analysis, employing the declining exponential approximation of life expectancy. Assumptions were put forth to bias the model in favor of cancer screening. Secondary comparisons were made between cancer screening and other interventions targeted to patients with ESRD. RESULTS: The costs per unit of survival benefit conferred by cancer screening were 1.6 to 19.3 times greater among patients with ESRD than in the general population, depending on age, sex, and race, and assumptions outlined herein. For persons with ESRD, the net gain in life expectancy from a typical cancer screening program was calculated to be 5 days or less. Similar survival gains could be obtained via a reduction of 0.02% or less in the baseline ESRD-related mortality rate. CONCLUSIONS: These analyses suggest that routine cancer screening in the population with ESRD is a relatively inefficient allocation of financial resources. Direction of funds toward improving the quality of dialysis could attain such an objective at substantially lower cost. Furthermore, these findings highlight the importance of competing risks as a consideration in the evaluation of screening strategies and other interventions targeted to patients with ESRD and to other populations with chronic diseases associated with reduced survival.

Prevention of human immunodeficiency virus-related opportunistic infections in France: a cost-effectiveness analysis.

A simulation model of human immunodeficiency virus (HIV) disease, which incorporated French data on the progression of HIV disease in the absence of antiretroviral therapy and on cost, was used to determine the clinical impact and cost-effectiveness of different strategies for the prevention of opportunistic infections in French patients who receive highly active antiretroviral therapy (HAART). Compared with use of no prophylaxis, use of trimethoprim-sulfamethoxazole (TMP-SMZ) increased per-person lifetime costs from euro 185,600 to euro 187,900 and quality-adjusted life expectancy from 112.2 to 113.7 months, for an incremental cost-effectiveness ratio of euro 18,700 per quality-adjusted life-year (euro/QALY) gained. Compared with use of TMP-SMZ alone, use of TMP-SMZ plus azithromycin cost euro 23,900/QALY gained; adding fluconazole cost an additional euro 54,500/QALY gained. All strategies that included oral ganciclovir had cost-effectiveness ratios that exceeded euro 100,000/QALY gained. In the era of HAART, on the basis of French data, prophylaxis against Pneumocystis carinii pneumonia, toxoplasmic encephalitis, and Mycobacterium avium complex bacteremia is cost-effective. Prophylaxis against fungal and cytomegalovirus infections is less cost-effective than are other therapeutic options for HIV disease and should remain of lower priority.

Modeling zidovudine therapy: a cost-effectiveness analysis.

Zidovudine (ZDV), the first FDA-approved therapy for HIV/AIDS, poses a dilemma to the policymaker. On the one hand, ZDV extends the life of HIV-infected persons, producing a clear benefit. On the other hand, some fear that prolonging the lives of infected individuals may contribute to the increased spread of the virus and to a steep rise in the overall costs of AIDS to society. To address this issue, we present a simple model of ZDV therapy against a backdrop of HIV transmission in a population of sexually active, gay men. We find no basis for the fear of dramatic increases in the incidence of AIDS or its associated costs among gay men due to widespread ZDV distribution. On the contrary, our analysis suggests that ZDV therapy is cost-effective, particularly when it is accompanied by modest efforts to promote behavior change and prevention.

The epidemiological and economic consequences of AIDS clinical trials.

The Food and Drug Administration (FDA) must manage the delicate balance between speed and safety in the evaluation and approval of new drugs. To explore how these competing obligations might be formalized with respect to the AIDS epidemic, we present a simple decision-theoretic optimization model of the clinical trials process against a backdrop of HIV transmission. Our framework sheds light on such issues as the economic consequences of decisions, the potential savings of a new therapy, the costs to society of delay, the value of better information, and how and when to undertake a clinical trial. We believe that this article represents a first effort to unravel the tangled web of epidemiological, economic, and statistical considerations that plague this policy issue.

Incidence of primary opportunistic infections in two human immunodeficiency virus-infected French clinical cohorts.

BACKGROUND: Clinical guidelines for the prevention of opportunistic infections in human immunodeficiency virus (HIV)-infected individuals have been developed on the basis of natural history data collected in the USA. The objective of this study was to estimate the incidence of primary opportunistic infections in HIV-infected individuals in geographically distinct cohorts in France. METHODS: We conducted our study on 2664 HIV-infected patients from the Tourcoing AIDS Reference Centre and the hospital-based information system of the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine enrolled from January 1987 to September 1995 and followed through December 1995. We estimated: (1) CD4-adjusted incidence rates of seven primary opportunistic infections in the absence of prophylaxis for that specific infection or any antiretroviral drugs other than zidovudine; and (2) CD4 lymphocyte count decline. RESULTS: The highest incidence rates for all opportunistic infections studied occurred in patients with CD4 counts < 200/microl. With CD4 counts < 50/microl, the most common opportunistic infections were toxoplasmic encephalitis (12.6 per 100 person-years) and Pneumocystis carinii pneumonia (11.4 per 100 person-years). Mycobacterium tuberculosis was the least common opportunistic infection (< 5.0/100 person-years). Even with CD4 counts > 300/microl, cases of Pneumocystis carinii pneumonia and toxoplasmic encephalitis were reported. The mean CD4 lymphocyte decline per month was 4.6 cells/microl. There was a significant association between HIV risk behaviour and the incidence of cytomegalovirus infection, between calendar year and the incidence of Pneumocystis carinii pneumonia, toxoplasmic encephalitis and Candida esophagitis, and between geographical area and the incidence of Pneumocystis carinii pneumonia and cytomegalovirus infection. CONCLUSIONS: Geographical differences exist in the incidence of HIV-related opportunistic infections. These results can be used to define local priorities for prophylaxis of opportunistic infections.

The FDA and regulation of cost-effectiveness claims.

The Food and Drug Administration (FDA) has issued draft guidelines that would require more rigorous standards for making pharmacoeconomic claims. This paper critiques the guidelines and explores the objectives of market regulation for health-related cost and effectiveness information on pharmaceutical products. It argues that the FDA should proceed with caution and flexibility. In particular, regulations should recognize the potential usefulness of pharmacoeconomic information in helping health care decisionmakers make better-informed choices. They also should acknowledge the enhanced ability of those using the information to evaluate pharmacoeconomic studies and the degree to which the various players in the market can impose their own regulatory discipline.

Mathematical programming for the efficient allocation of health care resources.

Previous discussions of methods for the efficient allocation of health care resources subject to a budget constraint have relied on unnecessarily restrictive assumptions. This paper makes use of established optimization techniques to demonstrate that a general mathematical programming framework can accommodate much more complex information regarding returns to scale, partial and complete indivisibility and program interdependence. Methods are also presented for incorporating ethical constraints into the resource allocation process, including explicit identification of the cost of equity.

Cost effectiveness of prophylaxis for opportunistic infections in AIDS. An overview and methodological discussion.

Dramatic progress has recently been made in defining the pathogenesis and treatment of HIV infection. For the first time in the history of the AIDS epidemic, clinicians have at their disposal an understanding of the replication kinetics of HIV, reliable assays to measure viral load, an increasing number of effective agents to suppress viral replication and to reverse the process of immune system destruction, and a range of options for the treatment and prophylaxis of most of the major opportunistic infections in HIV disease. These remarkable advances are not without their costs, however. New antiretroviral therapies and opportunistic infection prophylaxis regimens impose considerable financial strain on public and private budgets for HIV patient care. They force decision-makers to confront a variety of competing considerations, including issues of length and quality of life, the risks of adverse effects and toxicities, and the dangers of promoting resistance. Questions regarding the continued appropriateness and efficiency of opportunistic infection prevention have prompted increased interest in studies of the cost effectiveness of HIV patient care. In this article, we reviewed the literature on the economic evaluation of prophylaxis for HIV-related complications. Section 1 provides background on recent scientific and clinical advances. Section 2 reviews the state-of-the-art understanding of the cost effectiveness of prophylaxis against specific opportunistic infections. Section 3 broadens the discussion to consider the more general question of optimal allocation of prophylaxis resources across competing opportunistic infections. In Section 4, we briefly examined the influence of cost-effectiveness evaluations on the development and refinement of clinical guidelines for HIV-related opportunistic infection prevention in the US. Section 5 presents some of the methodological challenges that arise in applying the methods of cost-effectiveness analysis to the particular case of opportunistic infection prevention in AIDS. We close, in Section 6, with a comment on directions for further research.

Why training is the key to successful guideline implementation.

The market for pharmacoeconomic analysis is rapidly expanding. Demand for experienced investigators seems to have outpaced the capacity of both the academic community and industry to train qualified practitioners. The result is that many professionals charged with producing and using cost-effectiveness and other drug-related economic evaluation studies may lack the basic skills required to carry out their duties. This, in turn, raises concerns regarding the credibility and integrity of the field as a whole. In our opinion, the adoption of self-imposed practice guidelines is a necessary first step in confronting these issues. However, the power of guidelines to promote responsible practice will be limited by the technical preparation of the analysts charged with adhering to them. A long term solution requires a collaborative commitment, on the part of both the academic community and the private sector, to targeted graduate training in pharmacoeconomic methods, and to the provision of ample opportunities for continuing professional education.

Five minutes with the Governor.

This paper aims to initiate a dialog among readers regarding the positioning and promotion of health-related decision analysis in the public sector. It is motivated by the author's personal observations that quantitative and economic evaluation methods continue to be viewed with skepticism by some public officials and that no consensus exists within our community as to what an appropriate message to such decision makers might be. A personal view of some key themes to be stressed in defining a vision for the field is presented.

Estimating CE ratios under second-order uncertainty: the mean ratio versus the ratio of means.

Two methods have been presented for estimating cost-effectiveness ratios under conditions of second-order (model) uncertainty: one method estimates a mean ratio of cost to effect (the "mean ratio" approach), and the other estimates a ratio of mean cost to mean effect (the "ratio of means" approach). However, the question of which estimate is theoretically correct has not been formally addressed. The authors show that the "ratio of means" approach follows directly from the theoretical foundations of cost-effectiveness analysis, has attractive internal consistency properties, and is consistent with a simple vector algebra approach to the problem. In contrast, the "mean ratio" approach has not been shown to follow from first principles, is internally inconsistent, and can prescribe economically inefficient choices. It is concluded that the "ratio of means" procedure should be preferred unless persuasive arguments are presented to the contrary.

The cost-effectiveness of HIV testing: accounting for differential participation rates.

OBJECTIVE: To understand the impact of differences in participation rates between infected and uninfected individuals on estimates of the cost-effectiveness of HIV screening. METHODS: Costs per infection detected are modeled as function of both prevalence and serostatus-dependent testing rates. Data from national surveillance surveys, seroprevalence studies, and other sources are employed to suggest the magnitude of results. RESULTS: Differential participation produces a near-doubling in the estimated cost per infection identified. This result is sensitive to assumptions regarding the benefits of screening for seronegatives. CONCLUSIONS: Voluntary HIV screening programs may incur prohibitive costs by over-recruiting people at little risk of infection. Failure to account for differential participation can result in over-optimistic cost-effectiveness estimates. However, the relevance of this result--and the significance of both prevalence and participation as cost drivers--is overwhelmed by what is assumed about the benefits conferred to uninfected people by HIV screening.

The cost-effectiveness of fluconazole prophylaxis against primary systemic fungal infections in AIDS patients.

OBJECTIVE: To project the cost-effectiveness of fluconazole for prophylaxis against AIDS-related primary systemic fungal infections. DESIGN: A Markov model with data from the literature. PATIENTS: Hypothetical cohort of 100,000 AIDS patients. INTERVENTION: No prophylaxis, and fluconazole prophylaxis beginning when a patient's CD4 count declined to below 200/mm3, below 100/mm3, or below 50/mm3. RESULTS: The no-prophylaxis policy was associated with a discounted life expectancy of 28.20 months and direct medical costs of $36,100 per person. The < 200/mm3 strategy increased costs to $40,500 and life expectancy to 28.42 months, producing a ratio of $240,000 per year of life saved (YLS). Compared with the no-prophylaxis and < 200/mm3 policies, the intermediate alternatives were less economically efficient. A reduction in fluconazole's cost from $206 to $80 decreased the ratio to $50,000 for the < 200/mm3 strategy. Doubling fungal infection incidence lowered this ratio to $96,000/YLS. CONCLUSIONS: Fluconazole prophylaxis is unlikely to be cost-effective unless its cost is lowered, or it is focused on patients in regions endemic for fungal infections.