Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

A comparison of electronic and manual fracture risk assessment tools in screening elderly male US veterans at risk for osteoporosis.

This study compares four screening tools in their ability to predict osteoporosis. We found that there was no significant difference between the tools. These results provide support for the use of automated screening tools which work in conjunction with the electronic medical record and help improve screening rates for osteoporosis. INTRODUCTION: The purpose of this study is to compare the performance of four fracture risk assessment tools (FRATs) in identifying osteoporosis by bone mineral density (BMD) T-score: Veterans Affairs Fracture Absolute Risk Assessment Tool (VA-FARA), World Health Organization's Fracture Risk Assessment Tool (FRAX), electronic FRAX (e-FRAX), and Osteoporosis Self-Assessment Screening Tool (OST). METHODS: We performed a cross-sectional analysis of all patients enrolled in the VA Salt Lake City bone health team (BHT) who had completed a DXA scan between February 1, 2012, and February 1, 2013. DXA scan results were obtained by chart abstraction. For calculation of FRAX, osteoporosis risk factors were obtained from a screening questionnaire completed prior to DXA. For VA-FARA and e-FRAX, risk factors were derived from the electronic medical record (EMR). Clinical risk scores were calculated and compared against the gold standard of DXA-based osteoporosis. Sensitivity, specificity, and predictive values were calculated. Receiver operator characteristic (ROC) curves were plotted, and areas under the curve (AUC) were compared. RESULTS: A cohort of 463 patients met eligibility criteria (mean age 80.4 years). One hundred twelve patients (24%) had osteoporosis as defined by DXA T-score ≤-2.5. Sensitivity, specificity, and predictive values were calculated. ROC statistics were compared and did not reach statistical significance difference between FRATs in identifying DXA-based osteoporosis. CONCLUSIONS: Our study suggests that all FRATs tested perform similarly in identifying osteoporosis among elderly, primarily Caucasian, male veterans. If these electronic screening methods perform similarly for fracture outcomes, they could replace manual FRAX and thus improve efficiency in identifying individuals who should be sent for DXA scan.

Analysis of osteoporosis treatment patterns with bisphosphonates and outcomes among postmenopausal veterans.

PURPOSE: Adherence and persistence with bisphosphonates are frequently poor, and stopping, restarting, or switching bisphosphonates is common. We evaluated bisphosphonate change behaviors (switching, discontinuing, or reinitiating) over time, as well as fractures and costs, among a large, national cohort of postmenopausal veterans. METHODS: Female veterans aged 50+ treated with bisphosphonates during 2003-2011 were identified in Veterans Health Administration (VHA) datasets. Bisphosphonate change behaviors were characterized using pharmacy refill records. Patients' baseline disease severity was characterized based on age, T-score, and prior fracture. Cox Proportional Hazard analysis was used to evaluate characteristics associated with discontinuation and the relationship between change behaviors and fracture outcomes. Generalized estimating equations were used to evaluate the relationship between change behaviors and cost outcomes. RESULTS: A total of 35,650 patients met eligibility criteria. Over 6800 patients (19.1%) were non-switchers. The remaining patients were in the change cohort; at least half displayed more than one change behavior over time. A strong, significant predictor of discontinuation was ≥5 healthcare visits in the prior year (11-23% more likely to discontinue), and discontinuation risk decreased with increasing age. No change behaviors were associated with increased fracture risk. Total costs were significantly higher in patients with change behaviors (4.7-19.7% higher). Change-behavior patients mostly had significantly lower osteoporosis-related costs than non-switchers (22%-118% lower). CONCLUSIONS: Most bisphosphonate patients discontinue treatment at some point, which did not significantly increase the risk of fracture in this majority non-high risk population. Bisphosphonate change behaviors were associated with significantly lower osteoporosis costs, but significantly higher total costs.

Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection.

Clostridium difficile infection (CDI) is costly. Current guidelines recommend metronidazole as first-line therapy and vancomycin as an alternative. Recurrence is common. Faecal microbiota transplantation (FMT) is an effective therapy for recurrent CDI (RCDI). This study explores the cost-effectiveness of FMT, vancomycin and metronidazole for initial CDI. We constructed a decision-analytic computer simulation using inputs from published literature to compare FMT with a 10-14-day course of oral metronidazole or vancomycin for initial CDI. Parameters included cure rates (baseline value (range)) for metronidazole (80% (65-85%)), vancomycin (90% (88-92%)) and FMT(91% (83-100%)). Direct costs of metronidazole, vancomycin and FMT, adjusted to 2011 dollars, were $57 ($43-72), $1347 ($1195-1499) and $1086 ($815-1358), respectively. Our effectiveness measure was quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted from the third-party payer perspective. Analysis using baseline values showed that FMT($1669, 0.242 QALYs) dominated (i.e. was less costly and more effective) vancomycin ($1890, 0.241 QALYs). FMT was more costly and more effective than metronidazole ($1167, 0.238 QALYs), yielding an incremental cost-effectiveness ratio (ICER) of $124 964/QALY. One-way sensitivity analyses showed that metronidazole dominated both strategies if its probability of cure were >90%; FMT dominated if it cost <$584. In a probabilistic sensitivity analysis at a willingness-to-pay threshold of $100 000/QALY, metronidazole was favoured in 55% of model iterations; FMT was favoured in 38%. Metronidazole, as the first-line treatment for CDIs, is less costly. FMT and vancomycin are more effective. However, FMT is less likely to be economically favourable, and vancomycin is unlikely to be favourable as first-line therapy when compared with FMT.

Cost-effectiveness of training rural providers to identify and treat patients at risk for fragility fractures.

UNLABELLED: This is a cost-effectiveness analysis of training rural providers to identify and treat osteoporosis. Results showed a slight cost savings, increase in life years, increase in treatment rates, and decrease in fracture incidence. However, the results were sensitive to small differences in effectiveness, being cost-effective in 70 % of simulations during probabilistic sensitivity analysis. INTRODUCTION: We evaluated the cost-effectiveness of training rural providers to identify and treat veterans at risk for fragility fractures relative to referring these patients to an urban medical center for specialist care. The model evaluated the impact of training on patient life years, quality-adjusted life years (QALYs), treatment rates, fracture incidence, and costs from the perspective of the Department of Veterans Affairs. METHODS: We constructed a Markov microsimulation model to compare costs and outcomes of a hypothetical cohort of veterans seen by rural providers. Parameter estimates were derived from previously published studies, and we conducted one-way and probabilistic sensitivity analyses on the parameter inputs. RESULTS: Base-case analysis showed that training resulted in no additional costs and an extra 0.083 life years (0.054 QALYs). Our model projected that as a result of training, more patients with osteoporosis would receive treatment (81.3 vs. 12.2 %), and all patients would have a lower incidence of fractures per 1,000 patient years (hip, 1.628 vs. 1.913; clinical vertebral, 0.566 vs. 1.037) when seen by a trained provider compared to an untrained provider. Results remained consistent in one-way sensitivity analysis and in probabilistic sensitivity analyses, training rural providers was cost-effective (less than $50,000/QALY) in 70 % of the simulations. CONCLUSIONS: Training rural providers to identify and treat veterans at risk for fragility fractures has a potential to be cost-effective, but the results are sensitive to small differences in effectiveness. It appears that provider education alone is not enough to make a significant difference in fragility fracture rates among veterans.

Inpatient costs, mortality and 30-day re-admission in patients with central-line-associated bloodstream infections.

Previous work has suggested that central-line-associated bloodstream infection (CLABSI) is associated with increased costs and risk of mortality; however, no studies have looked at both total and variable costs, and information on outcomes outside of the intensive-care unit (ICU) is sparse. The aim of this study was to determine the excess in-hospital mortality and costs attributable to CLABSI in ICU and non-ICU patients. We conducted a retrospective cohort and cost-of-illness study from the hospital perspective of 398 patients at a tertiary-care academic medical centre from 1 January 2008 to 31 December 2010. All CLABSI patients and a simple random sample drawn from a list of all central lines inserted during the study period were included. Generalized linear models with log link and gamma distribution were used to model costs as a function of CLABSI and important covariates. Costs were adjusted to 2010 US dollars by use of the personal consumption expenditures for medical care index. We used multivariable logistic regression to identify independent predictors of in-hospital mortality. Among both ICU and non-ICU patients, adjusted variable costs for patients with CLABSI were c. $32 000 (2010 US dollars) higher on average than for patients without CLABSI. After we controlled for severity of illness and other healthcare-associated infections, CLABSI was associated with a 2.27-fold (95% CI 1.15-4.46) increased risk of mortality. Other healthcare-associated infections were also significantly associated with greater costs and mortality. Overall, CLABSI was associated with significantly higher adjusted in-hospital mortality and total and variable costs than those for patients without CLABSI.

Validated risk rule using computerized data to identify males at high risk for fracture.

UNLABELLED: Absolute risk assessment is now the preferred approach to guide osteoporosis treatment decisions. Data collected passively during routine healthcare operations can be used to develop discriminative absolute risk assessment rules in male veterans. These rules could be used to develop computerized clinical decision support tools that might improve fracture prevention. INTRODUCTION: Absolute risk assessment is the preferred approach to guiding treatment decisions in osteoporosis. Current recommended risk stratification rules perform poorly in men, among whom osteoporosis is overlooked and undertreated. A potential solution lies in clinical decision support technology. The objective of this study was to determine whether data passively collected in routine healthcare operations could identify male veterans at highest risk with acceptable discrimination. METHODS: Using administrative and clinical databases for male veterans ≥50 years old who sought care in 2005-2006, we created risk stratification rules for hip and any major fracture. We identified variables related to known or theoretical risk factors and created prognostic models using Cox regression. We validated the rules and estimated optimism. We created risk scores from hazards ratios and used them to predict fractures with logistic regression. RESULTS: The predictive models had C-statistics of 0.81 for hip and 0.74 for any major fracture, suggesting good to acceptable discrimination. For hip fracture, the cut-point that maximized percentage classified correctly (accuracy) predicted 165 of 227 hip fractures (73%) and missed 62 (27%). All hip fractures in patients with prior fracture were identified and 67% in patients without. For any major fracture, the maximal-accuracy cut-point predicted 611 of 987 (62%) and missed 376 (38%); the rule predicted all 134 fractures in patients with prior fracture and 56% in patients without. CONCLUSION: Data collected passively in routine healthcare operations can identify male veterans at highest risk for fracture with discrimination that exceeds that reported for other methods applied in men.

The cost-effectiveness of telestroke in the treatment of acute ischemic stroke.

OBJECTIVE: To conduct a cost-effectiveness analysis of telestroke--a 2-way, audiovisual technology that links stroke specialists to remote emergency department physicians and their stroke patients--compared to usual care (i.e., remote emergency departments without telestroke consultation or stroke experts). METHODS: A decision-analytic model was developed for both 90-day and lifetime horizons. Model inputs were taken from published literature where available and supplemented with western states' telestroke experiences. Costs were gathered using a societal perspective and converted to 2008 US dollars. Quality-adjusted life-years (QALYs) gained were combined with costs to generate incremental cost-effectiveness ratios (ICERs). In the lifetime horizon model, both costs and QALYs were discounted at 3% annually. Both one-way sensitivity analyses and Monte Carlo simulations were performed. RESULTS: In the base case analysis, compared to usual care, telestroke results in an ICER of $108,363/QALY in the 90-day horizon and $2,449/QALY in the lifetime horizon. For the 90-day and lifetime horizons, 37.5% and 99.7% of 10,000 Monte Carlo simulations yielded ICERs <$50,000/QALY, a ratio commonly considered acceptable in the United States. CONCLUSION: When a lifetime perspective is taken, telestroke appears cost-effective compared to usual care, since telestroke costs are upfront but benefits of improved stroke care are lifelong. If barriers to use such as low reimbursement rates and high equipment costs are reduced, telestroke has the potential to diminish the striking geographic disparities of acute stroke care in the United States.

Cost-effectiveness of adding decolonization to a surveillance strategy of screening and isolation for methicillin-resistant Staphylococcus aureus carriers.

We compared the cost-effectiveness of a methicillin-resistant Staphylococcus aureus (MRSA) programme of active surveillance plus decolonization with the current Veterans Health Administration (VHA) strategy of active surveillance alone, as well as a common strategy of no surveillance. A decision-analytical model was developed for an inpatient stay time horizon, using the VHA's perspective. Model inputs were taken from published literature where available, and supplemented with expert opinion when necessary. Effectiveness outcomes were hospital-acquired MRSA infections and deaths avoided. One-way and two-way sensitivity analyses and Monte Carlo simulations were performed. In the base-case analysis, the strategy of active surveillance plus decolonization dominated (i.e. lower cost and greater effectiveness) both the comparison strategies of active surveillance and no surveillance. In addition, the active surveillance strategy dominated the strategy of no surveillance. One-way and two-way sensitivity analyses demonstrated that at low levels of direct benefit of decolonization (1-4%), the strategy of active surveillance plus decolonization would no longer be dominant. In the probabilistic sensitivity analysis, active surveillance plus decolonization dominated both the other two strategies, and the active surveillance strategy dominated no surveillance in all of 1000 Monte Carlo simulations. These results provide a strong economic argument for adding an MRSA decolonization protocol to the current VHA active surveillance strategy.

Synthesis and bioaccessibility of Fe-pheophytin derivatives from crude spinach extract.

Heme iron is recognized as a highly bioavailable source of iron suitable for treatment of iron deficiency anemia. However, the animal origin of purified heme limits its broad applicability due to religious, personal, and food safety issues. Development of chlorophyll-derived heme mimetics offers opportunities to expand current iron fortification strategies. The objective of this study was the synthesis of Fe-pheophytin (FePhe) derivatives from natural chlorophyll and subsequent evaluation of their digestive behavior and bioaccessibility in vitro. FePhe a and a' were synthesized from crude spinach extracts by treatment with 1.3 M iron(II)chloride and 0.25 M Na-acetate dissolved in glacial acetic acid at 80 degrees C for 30 min. FePhe-rich extracts (approximately 1 mM) were formulated into corn starch based test meals (7.5% lipid) and subjected to a 2-step in vitro digestion designed to simulate in vivo gastric and small intestinal conditions. Recovery of FePhe following digestion and transfer of FePhe and pheophytins (Phe) from test meal matrix to mixed micelles was assessed by RP C18-HPLC to determine the digestive stability and micellarization efficiency (bioaccessibility). FePhe a and a' derivatives were moderately stable to digestive conditions with recoveries of 52.3% and 58.7%, respectively. Residual Phe a was stable to digestion. Micellarization efficiency of FePhe a (4%) and a' (3.4%) was significantly (P < 0.05) lower than Phe a (25.8%) from test meals. While digestive stability and micellarization efficiency are limiting, the presence of lipophilic FePhe derivatives in mixed micelles suggests that these compounds would be available for subsequent absorption in the intestinal tract.

Benchmarking in health-system pharmacy: experience at MeritCare Medical Center.

The experience of MeritCare Medical Center (MMC) with the Benchmarking Program coordinated by The Clinical Pharmacokinetics Laboratory at Millard Fillmore Hospital is described. MMC is a community-based teaching institution in Fargo, North Dakota, that serves patients in North Dakota, South Dakota, and Minnesota. MeritCare began participating in the Benchmarking Program in 1997. Data from the individual hospital report raised concern about the high cost of antimicrobials at MMC relative to peer-group institutions. The staff conducted an evaluation of antimicrobial prophylaxis for noncardiovascular surgery, concluded that cefazolin use was suboptimal, and attempted to encourage more cost-effective utilization. MMC's participation in the Benchmarking Program also prompted more appropriate use of various other antimicrobial agents, including i.v. and oral ciprofloxacin. An i.v.-to-oral switching program was begun for various agents. Preliminary analysis after 15 months demonstrated direct cost savings for drug acquisition of $60,000 to $80,000 per year and a reduced length of stay. Initiatives undertaken by MeritCare on the basis of data obtained through the Benchmarking Program resulted in substantial estimated savings in drug acquisition costs.

Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases.

Papilin is an extracellular matrix glycoprotein that we have found to be involved in, (1) thin matrix layers during gastrulation, (2) matrix associated with wandering, phagocytic hemocytes, (3) basement membranes and (4) space-filling matrix during Drosophila development. Determination of its cDNA sequence led to the identification of Caenorhabditis and mammalian papilins. A distinctly conserved 'papilin cassette' of domains at the amino-end of papilins is also the carboxyl-end of the ADAMTS subgroup of secreted, matrix-associated metalloproteinases; this cassette contains one thrombospondin type 1 (TSR) domain, a specific cysteine-rich domain and several partial TSR domains. In vitro, papilin non-competitively inhibits procollagen N-proteinase, an ADAMTS metalloproteinase. Inhibiting papilin synthesis in Drosophila or Caenorhabditis causes defective cell arrangements and embryonic death. Ectopic expression of papilin in Drosophila causes lethal abnormalities in muscle, Malpighian tubule and trachea formation. We suggest that papilin influences cell rearrangements and may modulate metalloproteinases during organogenesis.

An automated administration of Corsi's Block-tapping Test.

Corsi's Block-tapping Test has been a clinically useful test of visuospatial memory. Participants (15 men, 15 women) completed an automated and a manual version of the Block-tapping Test, the findings for which suggest that the automated and manual versions gave very similar scores.

Long-term pharmaceutical cost reduction using a data management system.

UNLABELLED: Cost containment is an important issue in medicine today, and the ability to control costs and maintain quality patient care presents a challenge to practitioners. Educating practitioners about drug costs has been identified as an effective method, but the benefits of education are usually short-lived. To evaluate the role of education in cost control, pharmaceutical use and performance improvement data were analyzed at a tertiary care institution during two time periods. A total of 4,530 anesthesia records and associated performance improvement data from March to June 1993 were analyzed as a baseline. These data were shared with the clinicians of an anesthesia department and used to educate practitioners regarding the costs and use of injectable pharmaceuticals and to identify areas in which cost savings could be achieved. The same information from 10,600 cases during January to October 1996 were compared with the early group. The expenditures for injectable pharmaceuticals to provide anesthesia were decreased by more than $30,000 per month, or $32 per case, without changing the performance indicators that were monitored, and has been maintained for >3 yr. IMPLICATIONS: By using a data management system, the cost for medications to provide anesthesia has been reduced without changing the quality of patient care.

Drosophila UDP-glucose:glycoprotein glucosyltransferase: sequence and characterization of an enzyme that distinguishes between denatured and native proteins.

A Drosophila UDP-glucose:glycoprotein glucosyltransferase was isolated, cloned and characterized. Its 1548 amino acid sequence begins with a signal peptide, lacks any putative transmembrane domains and terminates in a potential endoplasmic reticulum retrieval signal, HGEL. The soluble, 170 kDa glycoprotein occurs throughout Drosophila embryos, in microsomes of highly secretory Drosophila Kc cells and in small amounts in cell culture media. The isolated enzyme transfers [14C]glucose from UDP-[14C]Glc to several purified extracellular matrix glycoproteins (laminin, peroxidasin and glutactin) made by these cells, and to bovine thyroglobulin. These proteins must be denatured to accept glucose, which is bound at endoglycosidase H-sensitive sites. The unusual ability to discriminate between malfolded and native glycoproteins is shared by the rat liver homologue, previously described by A.J. Parodi and coworkers. The amino acid sequence presented differs from most glycosyltransferases. There is weak, though significant, similarity with a few bacterial lipopolysaccharide glycotransferases and a yeast protein Kre5p. In contrast, the 56-68% amino acid identities with partial sequences from genome projects of Caenorhabditis elegans, rice and Arabidopsis suggest widespread homologues of the enzyme. This glucosyltransferase fits previously proposed hypotheses for an endoplasmic reticular sensor of the state of folding of newly made glycoproteins.

Peroxidasin: a novel enzyme-matrix protein of Drosophila development.

Peroxidasin is a novel protein combining peroxidase and extracellular matrix motifs. Hemocytes differentiate early from head mesoderm, make peroxidasin and later phagocytose apoptotic cells. As hemocytes spread throughout the embryo, they synthesize extracellular matrix and peroxidasin, incorporating it into completed basement membranes. Cultured cells secrete peroxidasin; it occurs in larvae and adults. Each 1512 residue chain of the three-armed, disulfide-linked homotrimer combines a peroxidase domain with six leucine-rich regions, four Ig loops, a thrombospondin/procollagen homology and an amphipathic alpha-helix. The peroxidase domain is homologous with human myeloperoxidase and eosinophil peroxidase. This heme protein catalyzes H2O2-driven radioiodinations, oxidations and formation of dityrosine. We propose that peroxidasin functions uniquely in extracellular matrix consolidation, phagocytosis and defense.

Tiggrin, a novel Drosophila extracellular matrix protein that functions as a ligand for Drosophila alpha PS2 beta PS integrins.

Genetic and other studies of Drosophila integrins have implicated these extracellular matrix receptors in various morphogenetic events, but identification of their endogenous ligands has been elusive. We report the biochemical purification and cloning of tiggrin, a novel extracellular matrix protein from Drosophila. This 255 x 10(3) M(r) polypeptide contains the potential integrin recognition sequence Arg-Gly-Asp (RGD) and 16 repeats of a novel 73-77 amino acid motif. The tiggrin gene is at chromosome locus 26D1-2 and is expressed by embryonic hemocytes and fat body cells. Tiggrin protein is detected in matrices, especially at muscle attachment sites that also strongly express integrins. Tiggrin-coated surfaces support primary embryo cell culture and provide excellent substrates for alpha PS2 beta PS integrin-mediated cell spreading. Soluble RGD-peptides inhibit this cell spreading.