Predicting dysphagia onset in patients with ALS: the ALS dysphagia risk score.

Purpose: For patients diagnosed with ALS, dysphagia can result in aspiration, malnutrition, and mortality. The purpose of this study was to develop a clinical prediction model capable of identifying patients with ALS at imminent risk for developing swallowing complications. Methods: A retrospective cohort study using the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) was conducted. After dividing the PRO-ACT database into development and validation cohorts with dysphagia defined from the ALS Functional Rating Scale (ALSFRS), a multivariable Cox proportional hazards regression model estimated the probability of dysphagia at 3, 6, and 12-months with subsequent evaluation of model discrimination and calibration. Results: With 2057 participants in the development cohort and 1891 in the validation cohort, the Cox model included 7 clinical variables: spinal-onset; bulbar, fine and gross motor ALSFRS subscale scores; respiratory impairment; functional progression rate; and time from diagnosis. The cumulative incidence of dysphagia was 18% at 3-months, 29% at 6-months, and 45% at 12-months. The mean predicted probability of dysphagia development ranged from 4.5% in the bottommost risk decile to 40% in the topmost decile at 3 months, 10%-72% at 6 months, and 25%-93% at 12 months. In the validation cohort, the model had good discrimination and calibration with an optimism corrected c-statistic of 0.70 and calibration slope of 0.96. Conclusions: The ALS dysphagia risk score can be used to identify patients with ALS at high risk for self-reported dysphagia development who would benefit from a comprehensive swallowing assessment and proactive dysphagia management strategies.

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.

OBJECTIVE: To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. DATA SOURCES: We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1alpha-hydroxyvitamin D(3) (1alpha-hydroxycalciferol) or 1,25-dihydroxyvitamin D(3) (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. RESULTS: Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l v >or=60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). CONCLUSIONS: Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: We created and validated a Markov model to simulate the prognosis with treatment for HCV-related hepatocellular carcinoma (HCC) for assessment of cost-effectiveness for alternative treatments of HCC. METHOD: Markov state incorporated into the model consisted of the treatment as a surrogate for HCC stage and underlying liver function. Retrospective data of 793 patients from three university hospitals were used to determine Kaplan-Meier survival curves for each treatment and transition probabilities were derived from them. RESULTS: There was substantial overlap in the 95% CIs of the Markov model predicted and the Kaplan-Meier survival curves for each therapy. The predicted survival curves were also similar with those from the nationwide survey data supporting the external validity of our model. CONCLUSIONS: Our Markov model estimates for prognosis with HCC have both internal and external validity and should be considered applicable for estimating cost-effectiveness related to HCC.

Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States.

The aim of this work was to estimate the future disease burden of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in the United States until the year 2030. Two back-calculation models of the HIV and the HCV epidemic were developed. They were based on US epidemiological data regarding prevalence, age and gender of incident cases, AIDS, hepatocellular carcinoma (HCC) mortality and general population mortality from the Centers for Disease Control and WHO. Based on the HCV back-calculation model, HCV incidence peaked in 1984 at 350,000 new infections and then fell to about 77,000 in 1998. Based on the HIV back-calculation model, HIV incidence reached its maximum in 1989 at 142,000 new infections and then declined to 79,000 in 1998. Mortality related to HCV (death from liver failure or HCC) rose from about 3,700 in 1998 and is expected to peak at about 13,000 in 2030. Predicted HCV mortality would fall only if increased access to or more effective antiviral therapy occurs. For comparison, observed HIV-related mortality was 14,400 in 1998 and projected to be 4,200 for 2030. With the availability of effective highly active antiretroviral therapy for HIV infection, mortality from HIV appears to have declined substantially, whereas HCV-related deaths as a result of pre-1999 infections will likely continue to increase over the next 25 years.

Comparison of hemodialysis and peritoneal dialysis survival in The Netherlands.

Considerable geographic variation exists in the relative use of hemodialysis (HD) vs peritoneal dialysis (PD). Studies comparing survival between these modalities have yielded conflicting results. Our aim was to compare the survival of Dutch HD and PD patients. We developed Cox regression models using 16 643 patients from the Dutch End-Stage Renal Disease Registry (RENINE) adjusting for age, gender, primary renal disease, center of dialysis, year of start of renal replacement therapy, and included several interaction terms. We assumed definite treatment assignment at day 91 and performed an intention-to-treat analysis, censoring for transplantation. To account for time dependency, we stratified the analysis into three time periods, >3-6, >6-15, and >15 months. For the first period, the mortality hazard ratio (HR) of PD compared with HD patients was 0.26 (95% confidence interval (CI) 0.17-0.41) for 40-year-old non-diabetics, which increased with age and presence of diabetes to 0.95 (95% CI 0.64-1.39) for 70-year-old patients with diabetes as primary renal disease. The HRs of the second period were generally higher. After 15 months, the HR was 0.86 (95% CI 0.74-1.00) for 40-year-old non-diabetics and 1.42 (95% CI 1.23-1.65) for 70-year-old patients with diabetes as primary renal disease. We conclude that the survival advantage for Dutch PD compared with HD patients decreases over time, with age and in the presence of diabetes as primary disease.

[Health economics of chronic infectious diseases: the example of hepatitis C]. / Gesundheitsökonomische Aspekte chronischer Infektionskrankheiten am Beispiel der chronischen Hepatitis C.

Based on the German Hepatitis C Model (GEHMO) we developed a Hepatitis C Policy Model and applied it to the heterogeneous German hepatitis C population within the German health care context. We used Markov cohort simulation to predict absolute clinical and economic outcomes for a 20-year time horizon. For the cost-effectiveness analysis, a lifelong time horizon was used. Four different strategies were compared: (1) no antiviral treatment, (2) interferon monotherapy, (3) combination therapy with interferon plus ribavirin, and (4) combination therapy with pegylated interferon plus ribavirin. Based on our model, antiviral therapy with pegylated interferon and ribavirin could prevent about 17,000 cases of cirrhosis, 580 liver transplants, and 7,600 HCV-related deaths and is expected to save about 53,000 life years at total costs of 1.3 billion Euros within the next 20 years. Pegylated interferon plus ribavirin was the most effective treatment with an incremental cost-utility ratio of 23,000 Euros per quality-adjusted life year saved.

Analytic choices in economic models of treatments for rheumatoid arthritis: What makes a difference?

OBJECTIVES: To compare the analytic judgments, data, and assumptions of different models used in the economic evaluation of infliximab, one of a new class of drugs for rheumatoid arthritis (RA). METHODS: A detailed assessment was made of 4 models, 1 submitted (in a reimbursement dossier) by the manufacturer, 1 produced by an independent academic group, and 2 recently published in the literature. Factors considered included the key data inputs, assumptions about the sequencing of treatments for RA, the methods used to calculate health utilities, and the estimation of cost offsets. RESULTS: Two of the 4 models, although embodying different methodological approaches, gave fairly similar results (approximately 25,000 pounds- 35,000 pounds cost per additional quality-adjusted life year [QALY] gained). The other 2 models, both by an independent academic group, gave much higher estimates, ranging from 50,000 pounds to 60,000 pounds to more than 100,000 pounds per additional QALY. The differences appeared to depend mainly on differences in model structure, the assumptions about the positioning of infliximab in the treatment sequence, and the relationship between Health Assessment Questionnaire (HAQ) states and QALYs. CONCLUSIONS: Economic models of treatments for RA incorporate different key data inputs and analytic judgments. However, convergence was observed in some of the estimates produced by the models, particularly when adjustments were made for some of the differences in input parameters. Nevertheless, differences in the choice of model structure and in key assumptions also had a major impact on results. Therefore, more discussion is needed to reach a consensus on some of these methodological issues.

Cost-effectiveness of anti-tumor necrosis factor agents.

Rheumatoid arthritis can lead to substantial morbidity, disability and mortality. The development of anti-tumor necrosis factor antibodies from the bench to the bedside over the past 15 years has ushered in the new era of biologic therapies for rheumatic diseases. Etanercept, infliximab and adalimumab have all been approved for the treatment of rheumatoid arthritis on the basis of improved clinical outcomes. Because these treatments, however, are expensive and not uniformly effective, concerns have arisen regarding their cost-effectiveness. This paper reviews the disease burden of rheumatoid arthritis, costs of drug therapy, costs of rheumatoid arthritis and the economics and cost-effectiveness of anti-tumor necrosis factor antibody agents.

Cost-effectiveness of nucleic acid test screening of volunteer blood donations for hepatitis B, hepatitis C and human immunodeficiency virus in the United States.

BACKGROUND AND OBJECTIVES: The aim of this study was to examine the cost-effectiveness of adding nucleic acid testing (NAT) to serological (antibody and antigen) screening protocols for donated blood in the United States (US) with the purpose of reducing the risks of transfusion-transmission of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). MATERIALS AND METHODS: The costs, health consequences and cost-effectiveness of adding either minipool or individual-donor NAT to serological screening (SS) testing were estimated using a decision-analysis model. RESULTS: With the given modelling assumptions, adding minipool NAT would avoid an estimated 37, 128 and eight cases of HBV, HCV and HIV, respectively, and save approximately 53 additional years of life and 102 additional quality adjusted life years (QALYs) compared with SS, at a net cost of $154 million. SS + minipool NAT - p24 compared with SS alone resulted in an incremental cost-effectiveness ratio of $1.5 million per QALY gained (range in sensitivity analysis $1.0-2.1 million per QALY gained) in this US analysis. CONCLUSIONS: The cost effectiveness of adding NAT screening is outside the typical range for most healthcare interventions, but not for established blood safety measures.

A cost-effectiveness analysis of peginterferon alfa-2b plus ribavirin for the treatment of naive patients with chronic hepatitis C.

AIM: To estimate the cost-effectiveness of therapy and analyse the effect of therapy compliance in naive patients with chronic hepatitis C. METHODS: A decision analysis using the Markov model was performed for four different therapeutic strategies using peginterferon alfa-2b plus ribavirin or interferon alfa-2b plus ribavirin. Clinical data were obtained from available published reports and from the Spanish health system perspective. RESULTS: The incremental cost-effectiveness ratio of peginterferon alfa-2b plus ribavirin at a fixed dose, compared with interferon alfa-2b plus ribavirin, was 8478 euros per life year saved and 3737 euros per quality-adjusted life year gained. Good therapeutic compliance and weight-adjusted doses of ribavirin decreased the incremental cost-effectiveness ratio to 1636 euros per life year saved and 721 euros per quality-adjusted life year gained. In compliant genotype 1 patients, the incremental cost-effectiveness ratio decreased to 916 euros per life year saved and 404 euros per quality-adjusted life year gained, with an increase from 64 to 69 years in the threshold age at which therapy was cost-effective. The sensitivity analysis demonstrated that changes in the values of the most relevant parameters do not modify the study outcomes. CONCLUSION: From the clinical and pharmaco-economics perspective, the use of decision therapeutic analysis models suggests that the most effective therapy for chronic hepatitis C is peginterferon alfa-2b plus ribavirin adjusted to patient body weight and with good compliance, particularly in genotyped patients.

Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C.

BACKGROUND: Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. AIMS: To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. METHODS: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. CONCLUSIONS: Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

Strategies for diagnosing and treating suspected acute bacterial sinusitis: a cost-effectiveness analysis.

OBJECTIVE: Symptoms suggestive of acute bacterial sinusitis are common. Available diagnostic and treatment options generate substantial costs with uncertain benefits. We assessed the cost-effectiveness of alternative management strategies to identify the optimal approach. DESIGN: For such patients, we created a Markov model to examine four strategies: 1) no antibiotic treatment; 2) empirical antibiotic treatment; 3) clinical criteria-guided treatment; and 4) radiography-guided treatment. The model simulated a 14-day course of illness, included sinusitis prevalence, antibiotic side effects, sinusitis complications, direct and indirect costs, and symptom severity. Strategies costing less than 50,000 dollars per quality-adjusted life year gained were considered "cost-effective." MEASUREMENTS AND MAIN RESULTS: For mild or moderate disease, basing antibiotic treatment on clinical criteria was cost-effective in clinical settings where sinusitis prevalence is within the range of 15% to 93% or 3% to 63%, respectively. For severe disease, or to prevent sinusitis or antibiotic side effect symptoms, use of clinical criteria was cost-effective in settings with lower prevalence (below 51% or 44%, respectively); empirical antibiotics was cost-effective with higher prevalence. Sinus radiography-guided treatment was never cost-effective for initial treatment. CONCLUSIONS: Use of a simple set of clinical criteria to guide treatment is a cost-effective strategy in most clinical settings. Empirical antibiotics are cost-effective in certain settings; however, their use results in many unnecessary prescriptions. If this resulted in increased antibiotic resistance, costs would substantially rise and efficacy would fall. Newer, expensive antibiotics are of limited value. Additional testing is not cost-effective. Further studies are needed to find an accurate,low-cost diagnostic test for acute bacterial sinusitis.

Living-donor versus cadaveric liver transplantation for non-resectable small hepatocellular carcinoma and compensated cirrhosis: a decision analysis.

BACKGROUND: Cadaveric liver transplantation is effective for nonresectable early hepatocellular carcinoma. However, the scarcity of cadaveric organs has prompted some centers to use living donors, which guarantees transplantation, but entails a risk to the donor. In the absence of controlled trials, decision analysis can be used to help explicate the tradeoffs involved when considering living donor versus cadaveric liver transplantation for nonresectable early hepatocellular carcinoma. METHODS: Using a Markov model, a hypothetical cohort of patients with Child's A cirrhosis and a single 3.5-cm tumor received one of three strategies: 1) no transplant; 2) intent to perform cadaveric liver transplantation; or 3) living donor liver transplantation. Data were obtained from natural history and retrospective studies. All probabilities in the model were varied simultaneously using a Monte Carlo simulation. RESULTS: Living-donor liver transplantation was the best strategy, improving life expectancy by 4.5 years compared with cadaveric liver transplantation. This strategy remained dominant even when varying severity of cirrhosis, age, tumor doubling time, tumor growth pattern, blood type, regional transplant volume, initial tumor size, and rate of progression of cirrhosis. CONCLUSIONS: Living-donor liver transplantation should confer a substantial survival advantage for patients with compensated cirrhosis and non-resectable early stage hepatocellular carcinoma.

Using observational data to estimate prognosis: an example using a coronary artery disease registry.

With the proliferation of clinical data registries and the rising expense of clinical trials, observational data sources are increasingly providing evidence for clinical decision making. These data are viewed as complementary to randomized clinical trials (RCT). While not as rigorous a methodological design, observational studies yield important information about effectiveness of treatment, as compared with the efficacy results of RCTs. In addition, these studies often have the advantage of providing longer-term follow-up, beyond that of clinical trials. Hence, they are useful for assessing and comparing patients' long-term prognosis under different treatment strategies. For patients with coronary artery disease, many observational comparisons have focused on medical therapy versus interventional procedures. In addition to the well-studied problem of treatment selection bias (which is not the focus of the present study), three significant methodological problems must be addressed in the analysis of these data: (i) designation of the therapeutic arms in the presence of early deaths, withdrawals, and treatment cross-overs; (ii) identification of an equitable starting point for attributing survival time; (iii) site to site variability in short-term mortality. This paper discusses these issues and suggests strategies to deal with them. A proposed methodology is developed, applied and evaluated on a large observational database that has long-term follow-up on nearly 10 000 patients.

Cost-effectiveness of interferon alfa-2b with and without ribavirin as therapy for chronic hepatitis C in Sweden.

BACKGROUND: Recent trials have shown that treatment with a combination of interferon alfa-2b and ribavirin results in sustained loss of detectable hepatitis C-virus (HCV) RNA in a higher proportion of patients than treatment with interferon alone. Combination therapy, however, is two to three times as expensive as monotherapy. METHODS: Based on data from recent randomized clinical trials and a previously published decision model, we developed a Markov model to estimate the cost-effectiveness of initial combination therapy with interferon and ribavirin versus interferon alone for previously untreated patients with chronic HCV infection in Sweden. Clinical praxis and quality adjustments were based on expert estimates and costs were gathered from different health care providers in Sweden. RESULTS: Combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 0.5 to 1.1 years at marginal cost-effectiveness ratios of US$ 1,400 to US$ 6,000 per DQALY (discounted quality-adjusted life-year) for patients with genotype 1. In genotype 1, 48 weeks compared to 24 weeks of combination therapy prolonged quality adjusted life expectancy by 0.6 years at a marginal cost-effectiveness ratio of $US 9,800 per DQALY. For patients with genotype non-1, combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 2.3 years, with combination therapy for 24 weeks being money-saving. The results were robust in sensitivity analyses. CONCLUSION: Combination therapy with interferon and ribavirin increased quality-adjusted life expectancy and was cost-effective for patients with chronic hepatitis C.

A pragmatic and cost-effective strategy of a combination therapy of interferon alpha-2b and ribavirin for the treatment of chronic hepatitis C.

BACKGROUND: Combination of interferon (IFN) alpha and ribavirin is considered the standard treatment for patients with chronic hepatitis C. While combination therapy is more effective than IFN alone, the optimal management of combination treatment remains uncertain. OBJECTIVE: To assess a pragmatic and cost-effective strategy for the therapy of treatment-naive patients with chronic hepatitis C. DESIGN: Markov model on original data of two randomized trials. METHODS: A validated computer simulation model was applied to non-cirrhotic hepatitis C virus (HCV)-infected patients. Patient characteristics and efficacy of treatment were extracted from two randomized trials reporting on 1,445 non-cirrhotic patients. Different strategies were compared separately for genotype 1 and genotype non-1 (mostly genotype 2/3) infections: (1) no treatment; (2) IFN for 48 weeks (if at 12 weeks HCV RNA undetectable); (3) IFN and ribavirin for 24 weeks; (4) IFN and ribavirin for 48 weeks; (5) IFN and ribavirin for 48 weeks (if at 24 weeks HCV RNA undetectable). All strategies were tested for different combinations of known response factors. RESULTS: In genotype non-1 infection, 24 weeks of combination therapy dominates all other strategies. In genotype 1 infection, 48 weeks of combination therapy for week-24 responders only prolongs life expectancy at a favourable cost-effectiveness ratio (CE) of 7,135 euros per quality-adjusted life year (QALY). Taking response factors other than genotype into account does not add to the effectiveness or cost effectiveness. CONCLUSION: Treating non-cirrhotic patients with chronic hepatitis C according to genotype only is most cost effective independent of the number of other known response factors.

Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk.

PURPOSE: Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors. METHODS: We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists' Collaborative Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models. RESULTS: Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months. Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15). CONCLUSION: Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases.