Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study.

OBJECTIVE: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) in the United States compared to basic supportive therapy without DMT for patients with relapsing multiple sclerosis (MS). METHODS: Using data from a longitudinal MS survey, we generated 10-year disease progression paths for an MS cohort. We used first-order annual Markov models to estimate transitional probabilities. Costs associated with losses of employment were obtained from the Bureau of Labor Statistics. Medical costs were estimated using the Centers for Medicare and Medicaid Services reimbursement rates and other sources. Outcomes were measured as gains in quality-adjusted life-years (QALY) and relapse-free years. Monte Carlo simulations, resampling methods, and sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: Using DMT for 10 years resulted in modest health gains for all DMTs compared to treatment without DMT (0.082 QALY or <1 quality-adjusted month gain for glatiramer acetate, and 0.126-0.192 QALY gain for interferons). The cost-effectiveness of all DMTs far exceeded $800,000/QALY. Reducing the cost of DMTs had by far the greatest impact on the cost-effectiveness of these treatments (e.g., cost reduction by 67% would improve the probability of Avonex being cost-effective at $164,000/QALY to 50%). Compared to treating patients with all levels of disease, starting DMT earlier was associated with a lower (more favorable) incremental cost-effectiveness ratio compared to initiating treatment at any disease state. CONCLUSION: Use of DMT in MS results in health gains that come at a very high cost.

Selegiline shortage: Causes and costs of a generic drug shortage.

BACKGROUND: In September 2007, shortages of generic selegiline occurred, forcing patients to either switch to more expensive alternatives or forego treatment. We sought to evaluate prescription trends of generic selegiline and to quantify the economic impact of any resulting drug substitution of more expensive alternatives. METHODS: We analyzed proprietary data from IMS Health on monthly prescriptions in the United States for selegiline and potential substitutes from February 2002 through December 2007. Linear regression was used to predict the number of expected prescriptions after August 2007 had a shortage not occurred. The main outcome measures were the changes in prescriptions filled and the economic impact of drug substitution. RESULTS: Prior to the shortage, total prescriptions filled for generic selegiline decreased 42%, and supply consolidated into one company, Apotex Inc., Toronto, Canada, whose market share increased from 41% to 83%. During the first 4 months of the shortage, Apotex Inc. filled 10,500 fewer prescriptions than projected and other selegiline manufacturers filled 7,400 more than projected for a net shortage of 3,100 prescriptions. The number of branded selegiline capsules filled during this period increased by 1,800 above projections, and 1,300 prescriptions for generic selegiline were not refilled or substituted. The societal cost of substituting generic selegiline with branded capsules was $75,000 over the first 4 months of the shortage. CONCLUSIONS: Generic drug shortages carry economic and health implications. Given ongoing consolidation in the generics drug industry, these shortages may become more common and may require heightened regulatory scrutiny of the generic drug industry.

Invited Article: Conflicts of interest for authors of American Academy of Neurology clinical practice guidelines.

BACKGROUND: Clinical practice guidelines (CPGs) shape clinical care worldwide but are prone to potential error and bias due to conflicts of interest (COI). OBJECTIVE: To explore the extent and scope of American Academy of Neurology (AAN) guideline author reported COI and implications for management; and to review process of AAN guideline COI management to highlight challenges, establish comparative benchmarks, and identify areas to be improved. METHODS: Authors of AAN clinical practice guidelines with an active membership panel completed a COI reporting form. Authors were asked to report current interests including the 1 year prior to the date of completing the form. Interests include personal income relationships (consulting, speaker's bureaus, advisory boards), equity (stocks/stock options), patent/royalties, research, clinical practice, fiduciary interest in a company, and expert testimony. Comparisons were made between the two committees that oversee CPG development at the AAN: the Quality Standards Subcommittee (QSS) and the Therapeutics and Technology Assessment (TTA) Subcommittee. RESULTS: There were 50 CPG with an average of 8.5 authors per CPG. There were a total of 425 available authors, 351 of whom completed a COI reporting form (83% response rate). Forty-six of the 50 guidelines had at least one author with a COI. The most commonly reported COIs were research-related (45% of authors), clinical practice-related (42%), and personal income relationships (33%). Authors of QSS guidelines were more likely to have personal income COIs with pharmaceutical and medical device companies (39% vs 24%, p < 0.01), whereas authors of TTA guidelines were more likely to have clinical practice-related COIs (50% vs 38%, p < 0.05). A minority of authors had individual COIs exceeding >$25,000 or had multiple interests (>10) that overlapped with content of the guidelines. CONCLUSION: Conflicts of interest are common for authors of American Academy of Neurology clinical practice guidelines across many domains of personal and professional interests. More research is needed to improve the methods to identify and quantify the types of conflicts and their potential biasing effects on selecting guideline topics, grading research evidence, and formulating practice recommendations.

Quantitative risk-benefit analysis of natalizumab.

OBJECTIVE: To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS). METHODS: We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences. Patient cohorts treated with no disease-modifying treatment, natalizumab, subcutaneous interferon beta-1a, and a theoretical "perfect" MS treatment were modeled. Sensitivity analysis was used to explore model uncertainty, including varying risks of developing progressive multifocal leukoencephalopathy (PML). RESULTS: Treatment with natalizumab resulted in 9.50 QALYs over a 20-year time horizon, a gain of 0.80 QALYs over the untreated cohort and 0.38 QALYs over interferon beta-1a. The health loss due to PML was small (-0.06 QALYs). To offset natalizumab's incremental health gain over interferon beta-1a, the risk had to increase from 1 to 7.6 PML per 1,000 patients treated over 17.9 months. The "perfect" MS treatment accumulated 10.59 QALYs over the 20-year time horizon, 1.89 QALYs above the untreated cohort. Interferon beta-1a resulted in greater QALY gains compared with natalizumab if natalizumab's relative relapse reduction was reduced from 68% to 35% or if interferon beta-1a's relative reduction was increased from 32% to 65%. CONCLUSIONS: A more than sevenfold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab's health gain below that of interferon beta-1a, and there remains considerable room for additional gains in health (>50%) beyond those already achieved with current therapies.

Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis.

Using published data, we quantified the risk and benefits of natalizumab in relapsing multiple sclerosis using quality-adjusted life years (QALYs) as a metric. Over the first 2 years of therapy, the negative health effects from progressive multifocal leukoencephalopathy were small (loss of 0.001 QALYs) relative to the positive effects on relapses and disability resulting in 0.033 QALYs (12 quality-adjusted days) gained. For context, we performed an analogous calculation for interferon beta-1a, which also had a net health benefit of 0.033 QALYs (12 quality-adjusted days).

Health care costs decline after successful epilepsy surgery.

BACKGROUND: Surgery is an effective, high-cost procedure used increasingly to treat refractory epilepsy. For surgery to be cost-effective, long-term cost savings from reduced health care use should provide some offset to the initial costs of evaluation and surgery. There is little information about how health care costs are affected by evaluation and surgery. OBJECTIVE: To determine whether health care costs change when seizures become controlled after surgery. METHODS: Health care costs for the 2 years prior to surgical evaluation and for 2 years afterward were calculated from medical records of 68 subjects with temporal lobe epilepsy (TLE) participating in a multicenter observational study. Costs were compared among patients who did not have surgery, patients who had persisting seizures after surgery, and patients who were seizure free after surgery. RESULTS: Antiepileptic drugs (AEDs) accounted for more than half of the costs of care in the pre-evaluation period. Total costs for seizure-free patients had declined 32% by 2 years following surgery due to less use of AEDs and inpatient care. Costs did not change in patients with persisting seizures, whether they had surgery or not. In the 18 to 24 months following evaluation, epilepsy-related costs were $2,068 to $2,094 in patients with persisting seizures vs $582 in seizure-free patients. CONCLUSIONS: Costs remain stable over 2 years post-evaluation in patients with temporal lobe epilepsy whose seizures persist, but patients who become seizure free after surgery use substantially less health care than before surgery. Further cost reductions in seizure-free patients can be expected as antiepileptic drugs are successfully eliminated.

Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030.

Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe's 5 most and the world's 10 most populous nations. The number of individuals with PD over age 50 in these countries was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030.

Volunteering for early phase gene transfer research in Parkinson disease.

BACKGROUND: For early phase trials of novel interventions-such as gene transfer for Parkinson disease (PD)--whose focus is primarily on safety and tolerability, it is important that participants have a realistic understanding of the goals of such research. Recently, some have expressed concern that patients with PD may have unrealistic expectations. METHODS: The authors examined why patients with PD might volunteer for invasive early phase research by interviewing 92 patients with PD and comparing those who would (n = 46) and those who would not (n = 46) participate in a hypothetical phase I gene-transfer study. RESULTS: The two groups' demographic, clinical, functional, and quality of life measures, as well as their understanding of the research protocol, were similar. The groups did not differ on their perception of potential for personal benefit nor on the level of likelihood of benefit they saw as a precondition for volunteering. However, those willing to participate tended to perceive lower probability of risk, were tolerant of greater probability of risk, and were more optimistic about the phase I study's potential benefits to society. They also appeared more decisive and action-oriented than the unwilling group. CONCLUSIONS: It is likely that the decision whether to participate in early phase PD gene transfer studies will depend mostly on patients' attitudes regarding risk, optimism about science, and an action orientation, rather than on their clinical, functional, or demographic characteristics.

A Bayesian argument against rigid cut-offs in electrodiagnosis of median neuropathy at the wrist.

BACKGROUND: Nerve conduction (NC) tests, using rigid cut-offs separating normal from abnormal test values, are commonly used to confirm median neuropathy at the wrist (MNW). The authors studied patients with clinically defined mild MNW and a normal median distal motor latency to determine 1) how much sensory or mixed NC test results increase (or decrease) the probability of MNW and 2) the NC test values required to confirm (or exclude) MNW for the range of pretest probabilities of MNW. METHODS: Palmar, digit 4 (D4), and digit 2 (D2) median NC tests were reviewed in 125 hands with mild carpal tunnel syndrome (CTS) and 100 control hands with musculoskeletal pain. Receiver operating characteristic curves and interval likelihood ratios were plotted for the three tests. Using Bayes theorem, post-test probability of MNW was then determined for the range of pretest probabilities and NC test values. RESULTS: Receiver operating characteristic curves showed that for a set specificity of 97%, palmar and D4 studies had higher electrodiagnostic utility than D2 studies with cut-off test values (sensitivities of 0.3 msec, 64.0%; 0.4 msec, 71.2%; and 50 m/sec, 44.8%). However, Bayesian analysis showed that to confirm MNW more conservative cut-off values (palmar 0.5 msec, D4 0.7 msec, D2 44 m/sec) were required for pretest probabilities or=75%. Conversely, normal test values could exclude MNW only for pretest probabilities <25%. CONCLUSIONS: For a given NC test value, post-test probability of MNW can be determined from the estimated pretest probability (derived from clinical data), interval likelihood ratios, and Bayes theorem. Use of rigid cut-off values to confirm MNW is problematic, because more conservative cut-offs are required for low pretest probability. Conversely, NC tests with sensitivity <95% cannot exclude MNW when pretest probability is high.

Development of performance measures for acute ischemic stroke.

BACKGROUND AND PURPOSE: The purpose of the present study was to develop and rate performance measures for hospital-based acute ischemic stroke. METHODS: A national multidisciplinary panel of 16 individuals (2 stroke specialists, 2 general neurologists, 2 internists, 2 neuroscience nurses, 2 stroke advocacy organization representatives, 1 stroke rehabilitationist, 1 family practitioner, 1 emergency room physician, 1 neuroradiologist, 1 managed care organization director, and 1 hospital association representative) from 10 medical societies or lay organizations assisted in the development of 44 potential stroke performance measures. We developed evidence summaries for each of the performance measures and graded the level of evidence associated with each measure. The panel received a summary of the literature pertaining to each measure and rated the measures by use of a modified Delphi approach for 6 dimensions of quality, including validity of evidence, feasibility, impact on outcomes, room for improvement, plausibility, and an overall rating (little reason to do, could do, should do, and must do). RESULTS: Highly rated and agreed on performance measures for the overall rating include warfarin in atrial fibrillation, antithrombotics on hospital discharge, carotid imaging in appropriate patients, and use of stroke units. Additional measures notable for high agreement were heparins for deep-vein thrombosis prophylaxis and use of a stroke protocol. Panelists rated time-related thrombolytic measures such as head CT within 25 minutes highly on the room for improvement dimension but low on the overall dimension. Neurologists tended to rate measures lower than did nonneurologists (P<0.01) for all 9 measures pertaining to thrombolytic management. CONCLUSIONS: Highly rated and agreed on performance measures exist in all domains of hospital-based stroke care.

Deep brain stimulation in the treatment of Parkinson's disease: a cost-effectiveness analysis.

BACKGROUND: In treating PD, deep brain stimulation (DBS) has shown great promise in a series of uncontrolled studies. OBJECTIVE: To estimate the incremental cost effectiveness of DBS compared with the best medical management in late-stage PD. METHODS: The authors constructed a decision model to determine the lifetime incremental cost effectiveness between two options in patients with PD aged 50 years and older: 1) best medical management and 2) DBS. As the long-term efficacy of DBS (>3 years) is not known, key assumptions regarding the procedure's long-term durability were made. Costs were in US 2000 dollars, and quality-adjusted life year (QALY) was the effectiveness measure. Base assumptions were that quality of life (QOL) in patients with late-stage PD is 0.55 (0-to-1 scale, 1 is perfect health) and that DBS benefits are constant for 4 years, eroding gradually over the next 5 years until at parity with those produced by best medical management. Incremental cost-effectiveness and sensitivity analyses were performed. RESULTS: Under base-case assumptions, DBS provides an additional 0.72 QALY at an additional cost of $35,000 compared with best medical management that results in an incremental cost-effectiveness ratio (C/E) of $49,000. QOL increases of between 18 and 30% resulted in questionable cost effectiveness. QOL increases of between 6 and 18% resulted in incremental C/E ratios not usually considered cost effective (>100,000/QALY). CONCLUSIONS: The results suggest that DBS may be cost effective in treating PD if QOL improves 18% or more compared with those receiving best medical management. This underscores the need for randomized, controlled, prospective DBS experiments including QOL and economic components.

Neurologists' use of ICD-9CM codes for dementia.

Neurologists' use of ICD-9CM codes in a sample of 181 consecutive, new patients evaluated for dementia by 48 of all 49 neurologists from the Rochester, NY, area over a 1-year period was examined. The specific code for AD, 331.0, was used for only 36.5% of patients judged by the neurologist to have AD as the most likely diagnosis. Other codes used were not inaccurate but would result in lower reimbursement. Variation in coding could affect validity of dementia research using claims data.

Initial treatment of early Parkinson's disease: a review of recent, randomized controlled trials.

Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson's disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson's Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.

US neurologists: attitudes on rationing.

OBJECTIVE: To assess neurologists' attitudes on rationing health care and to determine whether neurologists would set healthcare priorities in ways that are consistent with cost-effectiveness research. BACKGROUND: Cost-effectiveness research can suggest ways to maximize health benefits within fixed budgets but is currently being underused in resource allocation decisions. METHODS: The authors surveyed a random sample of neurologists practicing in the United States (response rate, 44.4%) with three hypothetical scenarios. Two scenarios were designed to address general attitudes on allocating finite resources with emphasis on formulary decisions for costly drugs. The third scenario was designed to assess whether neurologists would optimize the allocation of a fixed budget as recommended by cost-effectiveness analysis. RESULTS: Three-quarters of respondents thought that neurologists make daily decisions that effectively ration healthcare resources, and 60% felt a professional responsibility to consider the financial impact of individualized treatment decisions on other patients. Only 25% of respondents thought that there should be no restrictions placed on any of the five newer antiepileptic agents. In a 1995 survey, 75% of similarly sampled neurologists agreed that no restrictions should be placed on the availability of FDA-approved medications. Nearly half (46%) of respondents favored a less effective test and would be willing to let patients die to ensure the offering of a more equitable alternative. CONCLUSIONS: Most neurologists recognize the need to ration health care, and although they think cost-effectiveness research is one method to achieve efficient distribution of resources, many think that considerable attention should also be given to equity.

Systematic review of clinical prediction rules for neuroimaging in the evaluation of dementia.

BACKGROUND: Clinical practice guidelines for dementia do not recommend routine neuroimaging but vary in their recommended clinical prediction rules to identify patients who should undergo neuroimaging for potentially reversible causes of dementia. METHODS: Using a MEDLINE search supplemented by other strategies, we identified studies from January 1, 1983, through December 31, 1998, that evaluated the diagnostic performance of a clinical prediction rule. We calculated the sensitivity and specificity of each rule, then evaluated their diagnostic performance in a hypothetical cohort of 1000 patients with dementia, varying the prevalence of potentially reversible dementia from 1% to 15%. RESULTS: We identified 7 studies that evaluated at least 1 of 6 different clinical prediction rules. Only one rule consistently had high sensitivity (>85%) across all studies; none consistently had high specificity (>85%). Six of the 7 studies included less than 15 cases of potentially reversible dementia; thus the sensitivity and specificity for each rule had relatively wide confidence intervals. At a 5% prevalence of potentially reversible dementia, all rules had low positive predictive value (<15%) in our hypothetical cohort. Depending on the rule, our analysis predicts 6 to 44 of the 50 patients with potentially reversible dementia (5% prevalence in cohort of 1000 patients) would not undergo imaging. CONCLUSIONS: There is considerable uncertainty in the evidence underlying clinical prediction rules to identify which patients with dementia should undergo neuroimaging. Application of these rules may miss patients with potentially reversible causes of dementia.

Stroke prevention: narrowing the evidence-practice gap.

Many interventions reduce stroke risk. However, the full benefits of these interventions are not realized at current levels of utilization, as nearly all evidence-based or guideline-endorsed stroke prevention services are underused. The cause for such underuse is multifactorial and includes factors relating to both patients and providers, as well as to a health care system that has de-emphasized prevention at the expense of acute, technologically based care. Much like the evidence for stroke interventions themselves, there is a growing literature to support methods of implementing research evidence into clinical practice. There is still much to learn, however, about the effectiveness of interventions aimed at achieving changes in stroke prevention practice or the delivery of stroke prevention care. Nevertheless, there are many opportunities for providers, managed care organizations, and government to close the evidence-practice gap that exists for stroke prevention services. These opportunities exist in both the inpatient and outpatient setting, and depend on the neurologist taking a leading role in emphasizing the critical importance of risk factor identification and modification in all patients at risk for stroke.