Martin Pitt

An analysis of the academic literature on simulation and modelling in health care

This article describes a multi-dimensional approach to the classification of the research literature on simulation and modelling in health care. The aim of the study was to analyse the relative frequency of use of a range of operational research modelling approaches in health care, along with the specific domains of application and the level of implementation. Given the vast scale of the health care modelling literature, a novel review methodology was adopted, similar in concept to the approach of stratified sampling. The results provide new insights into the level of activity across many areas of application, highlighting important relationships and pointing to key areas of omission and neglect in the literature. In addition, the approach presented in this article provides a systematic and generic methodology that can be extended to other application domains as well as other types of information source in health-care modelling.

Dasatinib and Nilotinib for Imatinib-Resistant or -Intolerant Chronic Myeloid Leukaemia: A Systematic Review and Economic Evaluation

BACKGROUND Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

On the challenges of healthcare modelling and a proposed project life-cycle for successful implementation

OR methods and tools are being increasingly applied within the health services domain to support objective decision-making for the effective and efficient provision of resources. Healthcare modelling, however, is beset with many challenges and this paper examines a number of issues that define the primary challenges faced by the modeller in this field. It is fair to say that their resolution determines the likely success or failure of healthcare modelling in general. Working with a number of participating health service organizations, a proposed framework towards successful implementation has evolved and is presented in this paper

The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model

OBJECTIVE To review the evidence for the effectiveness and cost-effectiveness of storing kidneys from deceased donors prior to transplantation, using cold static storage solutions or pulsatile hypothermic machine perfusion. DATA SOURCES Electronic databases were searched in January 2008 and updated in May 2008 for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs), other study designs and ongoing research. Sources included: Cochrane Library, MEDLINE, EMBASE, CINAHL, ISI Web of Knowledge, DARE, NRR, ReFeR, Current Controlled Trials, and (NHS) HTA. Bibliographies of articles were searched for further relevant studies, and the Food and Drugs Administration (FDA) and European Regulatory Agency Medical Device Safety Service websites were searched. Only English language papers were sought. REVIEW METHODS The perfusion machines identified were the LifePort Kidney Transporter (Organ Recovery Systems) and the RM3 Renal Preservation System (Waters Medical Systems). The cold storage solutions reviewed were: University of Wisconsin, ViaSpan; Marshalls hypertonic citrate, Soltran; and Genzyme, Celsior. Each intervention was compared with the others as data permitted. The population was recipients of kidneys from deceased donors. The main outcomes were measures of graft survival, patient survival, delayed graft function (DGF), primary non-function (PNF), discard rates of non-viable kidneys, health-related quality of life and cost-effectiveness. Where data permitted the results of studies were pooled using meta-analysis. A Markov (state transition) model was developed to simulate the main post-transplantation outcomes of kidney graft recipients. RESULTS Eleven studies were included: three full journal published RCTs, two ongoing RCTs [European Machine Preservation Trial (MPT) and UK Pulsatile Perfusion in Asystolic donor Renal Transplantation (PPART) study], one cohort study, three full journal published retrospective record reviews and two retrospective record reviews published as posters or abstracts only. For LifePort versus ViaSpan, no significant differences were found for DGF, PNF, acute rejection, duration of DGF, creatinine clearance or toxicity, patient survival or graft survival at 6 months, but graft survival was better at 12 months post transplant with machine perfusion (LifePort = 98%, ViaSpan = 94%, p < 0.03). For LifePort versus RM3, all outcomes favoured RM3, although the results may be unreliable. For ViaSpan versus Soltran, there were no significant differences in graft survival for cold ischaemic times up to 36 hours. For ViaSpan versus Celsior, no significant differences were found on any outcome measure. In terms of cost-effectiveness, data from the MPT suggested that machine preservation was cheaper and generated more quality-adjusted life-years (QALYs), while the PPART study data suggested that cold storage was preferable on both counts. The less reliable deterministic outputs of the cohort study suggested that LifePort would be cheaper and would generate more QALYs than Soltran. Sensitivity analyses found that changes to the differential kidney storage costs between comparators have a very low impact on overall net benefit estimates; where differences in effectiveness exist, dialysis costs are important in determining overall net benefit; DGF levels become important only when differences in graft survival are apparent between patients experiencing immediate graft function (IGF) versus DGF; relative impact of differential changes to graft survival for patients experiencing IGF as opposed to DGF depends on the relative proportion of patients experiencing each of these two outcomes. CONCLUSIONS The conclusions drawn for the comparison of machine perfusion with cold storage depend on which trial data are used in the model. Owing to the lack of good research evidence that either ViaSpan or Soltran is better than the other, the cheaper, Soltran, may be preferable. In the absence of a cost-utility analysis, the results of our meta-analysis of the RCTs comparing ViaSpan with Celsior indicate that these cold storage solutions are equivalent. Further RCTs of comparators of interest to allow for appropriate analysis of subgroups and to determine whether either of the two machines under consideration produces better outcomes may be useful. In addition, research is required to: establish the strength and reliability of the presumed causal association between DGF and graft, and patient survival; investigate the utility impacts of renal replacement therapy; determine what the additional cost, survival and QALY impacts are of decreased or increased non-viable kidneys when discarded pre transplantation; and identify a reliable measure for predicting kidney viability from machine perfusion.

A cost–utility analysis of microwave and thermal balloon endometrial ablation techniques for the treatment of heavy menstrual bleeding

Objective  To assess the cost effectiveness of the second‐generation surgical treatments for heavy menstrual bleeding (microwave and thermal balloon endometrial ablation) compared with existing endometrial ablation techniques (transcervical resection and rollerball, alone or in combination) and hysterectomy.

A cost‐utility analysis of pimecrolimus vs. topical corticosteroids and emollients for the treatment of mild and moderate atopic eczema

Background  Conventional treatments for atopic eczema include topical corticosteroids (TCS) and emollients. Pimecrolimus, an immunosuppressant, was licensed in the U.K. in 2003 as an alternative treatment of mild to moderate atopic eczema.

Maximizing the Population Benefit From Thrombolysis in Acute Ischemic Stroke A Modeling Study of In-Hospital Delays

Background and Purpose— To maximize the benefits of thrombolysis, it is necessary not only to treat more patients, but to deliver treatment as early as possible. The aims of our study were to prospectively evaluate the clinical benefit from reducing delays in the emergency stroke pathway at our district hospital and examine outcomes from scenarios that include extension of the alteplase license. Methods— We developed a discrete-event simulation from prospective data for patients with stroke arriving at our large district hospital. We modeled current practice and assessed the impact on stroke outcomes of measures to reduce in-hospital delays to alteplase treatment and of extensions to the European license for alteplase from 3 to 4.5 hours and to people aged >80 years. Results— Extension of the time window to 4.5 hours increases the thrombolysis rate by 4%, yielding an additional 2 patients per year with minimal or no disability at 3 months. Time window extension is most effective when combined with a system of prealerts, achieving a thrombolysis rate of 15% and an additional 8 patients per year with minimal or no disability, increasing to 13 patients per year with extension of the license to patients >80 years. Conclusions— If implemented alone, extension of the time window for alteplase has only a modest additional population disability benefit, but this benefit can be increased 5-fold if time window extension is combined with substantial reductions to in-hospital delays.

Screening injured children for physical abuse or neglect in emergency departments: a systematic review

BACKGROUND Screening markers are used in emergency departments (EDs) to identify children who should be assessed for possible physical abuse and neglect. We conducted three systematic reviews evaluating age, repeat attendance and injury type as markers for physical abuse or neglect in injured children attending EDs. METHODS We included studies comparing markers in physically abused or neglected children and non-abused injured children attending ED or hospital. We calculated likelihood ratios (LRs) for age group, repeat attendance and injury type (head injury, bruises, fractures, burns or other). Given the low prevalence of abuse or neglect, we considered that an LR of 10 or more would be clinically useful. RESULTS All studies were poor quality. Infancy increased the risk of physical abuse or neglect in severely injured or admitted children (LRs 7.7-13.0, 2 studies) but was not strongly associated in children attending the ED (LR 1.5, 95% CI: 0.9, 2.8; one study). Repeat attendance did not substantially increase the risk of abuse or neglect and may be confounded by chronic disease and socio-economic status (LRs 0.8-3.9, 3 studies). One study showed no evidence that the type of injury substantially increased the risk of physical abuse or neglect in severely injured children. CONCLUSIONS There was no evidence that any of the markers (infancy, type of injury, repeated attendance) were sufficiently accurate (i.e. LR >or= 10) to screen injured children in the ED to identify those requiring paediatric assessment for possible physical abuse or neglect. Clinicians should be aware that among injured children at ED a high proportion of abused children will present without these characteristics and a high proportion of non-abused children will present with them. Information about age, injury type and repeat attendances should be interpreted in this context.

Will Delays in Treatment Jeopardize the Population Benefit From Extending the Time Window for Stroke Thrombolysis

Background and Purpose— Pooled analyses show benefits of intravenous alteplase (recombinant tissue-type plasminogen activator) treatment for acute ischemic stroke up to 4.5 hours after onset despite marketing approval for up to 3 hours. However, the benefit from thrombolysis is critically time-dependent and if extending the time window reduces treatment urgency, this could reduce the population benefit from any extension. Methods— Based on 3830 UK patients registered between 2005 to 2010 in the Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis Registry (SITS-ISTR), a Monte Carlo simulation was used to model recombinant tissue-type plasminogen activator treatment up to 4·5 hours from onset and assess the impact (numbers surviving with little or no disability) from changes in hospital treatment times associated with this extended time window. Results— We observed a significant relation between time remaining to treat and time taken to treat in the UK SITS-ISTR data set after adjustment for censoring. Simulation showed that as this “deadline effect” increases, an extended treatment time window entails that an increasing number of patients are treated at a progressively lower absolute benefit to a point where the population benefit from extending the time window is entirely negated. Conclusions— Despite the benefit for individual patients treated up to 4.5 hours after onset, the population benefit may be reduced or lost altogether if extending the time window results in more patients being treated but at a lower absolute benefit. A universally applied reduction in hospital arrival to treatment times of 8 minutes would confer a population benefit as large as the time window extension.

Systems modelling and simulation in health service design, delivery and decision making

The ever increasing pressures to ensure the most efficient and effective use of limited health service resources will, over time, encourage policy makers to turn to system modelling solutions. Such techniques have been available for decades, but despite ample research which demonstrates potential, their application in health services to date is limited. This article surveys the breadth of approaches available to support delivery and design across many areas and levels of healthcare planning. A case study in emergency stroke care is presented as an exemplar of an impactful application of health system modelling. This is followed by a discussion of the key issues surrounding the application of these methods in health, what barriers need to be overcome to ensure more effective implementation, as well as likely developments in the future.