745 resultados para cost benefit analysis


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Healthcare providers and policy makers are faced with an ever-increasing number of medical publications. Searching for relevant information and keeping up to date with new research findings remains a constant challenge. It has been widely acknowledged that narrative reviews of the literature are susceptible to several types of bias and a systematic approach may protect against these biases. The aim of this thesis was to apply quantitative methods in the assessment of outcomes of topical therapies for psoriasis. In particular, to systematically examine the comparative efficacy, tolerability and cost-effectiveness of topical calcipotriol in the treatment of mild-to-moderate psoriasis. Over the years, a wide range of techniques have been used to evaluate the severity of psoriasis and the outcomes from treatment. This lack of standardisation complicates the direct comparison of results and ultimately the pooling of outcomes from different clinical trials. There is a clear requirement for more comprehensive tools for measuring drug efficacy and disease severity in psoriasis. Ideally, the outcome measures need to be simple, relevant, practical, and widely applicable, and the instruments should be reliable, valid and responsive. The results of the meta-analysis reported herein show that calcipotriol is an effective antipsoriatic agent. In the short-tenn, the pooled data found calcipotriol to be more effective than calcitriol, tacalcitol, coal tar and short-contact dithranol. Only potent corticosteroids appeared to have comparable efficacy, with less short-term side-effects. Potent corticosteroids also added to the antipsoriatic effect of calcipotriol, and appeared to suppress the occurrence of calcipotriol-induced irritation. There was insufficient evidence to support any large effects in favour of improvements in efficacy when calcipotriol is used in combination with systemic therapies in patients with severe psoriasis. However, there was a total absence of long-term morbidity data on the effectiveness of any of the interventions studied. Decision analysis showed that, from the perspective of the NHS as payer, the relatively small differences in efficacy between calcipotriol and short-contact dithranol lead to large differences in the direct cost of treating patients with mildto-moderate plaque psoriasis. Further research is needed to examine the clinical and economic issues affecting patients under treatment for psoriasis in the UK. In particular, the maintenance value and cost/benefit ratio for the various treatment strategies, and the assessment of patient's preferences has not yet been adequately addressed for this chronic recurring disease.

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BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

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Thesis (Master's)--University of Washington, 2016-08

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Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização de Estruturas

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Background: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. Methods: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. Results: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. Conclusion: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well. © Lange et al.

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Background: Rotavirus diarrhea is one of the most important causes of death among under-five children. Anti-rotavirus vaccination of these children may have a reducing effect on the disease. Objectives: this study is intended to contribute to health policy-makers of the country about the optimal decision and policy development in this area, by performing cost-effectiveness and cost-utility analysis on anti-rotavirus vaccination for under-5 children. Patients and Methods: A cost-effectiveness analysis was performed using a decision tree model to analyze rotavirus vaccination, which was compared with no vaccination with Iran’s ministry of health perspective in a 5-year time horizon. Epidemiological data were collected from published and unpublished sources. Four different assumptions were considered to the extent of the disease episode. To analyze costs, the costs of implementing the vaccination program were calculated with 98% coverage and the cost of USD 7 per dose. Medical and social costs of the disease were evaluated by sampling patients with rotavirus diarrhea, and sensitivity analysis was also performed for different episode rates and vaccine price per dose. Results: For the most optimistic assumption for the episode of illness (10.2 per year), the cost per DALY averted is 12,760 and 7,404 for RotaTeq and Rotarix vaccines, respectively, while assuming the episode of illness is 300%, they will be equal to 2,395 and 354, respectively, which will be highly cost-effective. Number of life-years gained is equal to 3,533 years. Conclusions: Assuming that the illness episodes are 100% and 300% for Rotarix and 300% for Rota Teq, the ratio of cost per DALY averted is highly cost-effective, based on the threshold of the world health organization (< 1 GDP per capita = 4526 USD). The implementation of a national rotavirus vaccination program is suggested.

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A partir del análisis crítico de diversas teorías del riesgo propuestas por autores como Paul Slovic, CassSunstein, Mary Douglas y Ulrich Beck, este artículo delinea algunos fundamentos para una teoría posmarxista del riesgo. Contra cualquier pretendida "Sociedad Mundial del Riesgo" se identificará una específica Lógica del Riesgo capaz de poseer alcance mundial pero que, más allá de su vocación utópica, es concebida como incapaz de lograr el cierre final de lo social, ya sea mediante los instrumentos de un "Estado costo-beneficio" o del desenvolvimiento dialéctico necesario de la sociedad industrial.

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A partir del análisis crítico de diversas teorías del riesgo propuestas por autores como Paul Slovic, CassSunstein, Mary Douglas y Ulrich Beck, este artículo delinea algunos fundamentos para una teoría posmarxista del riesgo. Contra cualquier pretendida "Sociedad Mundial del Riesgo" se identificará una específica Lógica del Riesgo capaz de poseer alcance mundial pero que, más allá de su vocación utópica, es concebida como incapaz de lograr el cierre final de lo social, ya sea mediante los instrumentos de un "Estado costo-beneficio" o del desenvolvimiento dialéctico necesario de la sociedad industrial.

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A partir del análisis crítico de diversas teorías del riesgo propuestas por autores como Paul Slovic, CassSunstein, Mary Douglas y Ulrich Beck, este artículo delinea algunos fundamentos para una teoría posmarxista del riesgo. Contra cualquier pretendida "Sociedad Mundial del Riesgo" se identificará una específica Lógica del Riesgo capaz de poseer alcance mundial pero que, más allá de su vocación utópica, es concebida como incapaz de lograr el cierre final de lo social, ya sea mediante los instrumentos de un "Estado costo-beneficio" o del desenvolvimiento dialéctico necesario de la sociedad industrial.

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The central objective of this case study was to formulate the strategy of internationalization of Tubofuro®, discriminating relevant points from its design to its implementation. This is a company located in Leiria, Ortigosa parish, which operates, among others, in the Portuguese PVC pipes industry for which currently the domestic market is clearly insufficient, given the oversupply compared to demand. Being Tubofuro® an exporting company since 2004, the work here developed specifically intended to increase sales to the foreign market, with this representing 45% of total company's business in 2018 increasing of the number of markets through new partners to enable the positioning of Tubofuro® among the main players in each market, particularly in South American markets, North African and European. To achieve the above objectives presented a case study was applied, centred on Tubofuro® company, target of the internationalization strategy. The search carried out for the formulation of the strategy has been supported on a thorough analysis of the external environment and internal characteristics of the company, for which were crossed different types of data, quantitative, qualitative, secondary data and primary data. From this work resulted the development of internationalization and international marketing plan for the next three years, whose objectives are based on entrance and consequent growth in new markets, including the market Chilean, Peruvian, Mexican, Argentine, Algerian and German, as well growth in the presence and turnover in the markets for which Tubofuro® already exports regularly, for example Spain, France, Tunisia and Morocco. Based on the production capacity of Tubofuro® company, which will not suffer any kind of investment for incrementing but only to update, it is expected that the appropriate response capacity for the company is 8 regular markets, and could eventually arise sporadic exports to other markets not interfering with the normal production capacity of the company. The suggestion of the presented markets resulted from the study of the final price based on the one that local customers purchase a product equal or similar to Tubofuro® and the number of potential existing customers in each market. The internationalization model known as Uppsala Model corresponds to the strategy adopted by the company to its internationalization process, taking into account the philosophy of senior management and the risk aversion of them. The sales team Tubofuro® demand for each market, export a full container registering customer feedback, including quality and flow capacity in the market in order to seek a partnership agreement with a local distributor, which allows the Tubofuro® go to step two above mentioned model. The partnership agreement is based on mutual commitment to technical cooperation and trade between the Tubofuro® and partner, in order to increase the performance capacity among local customers. Only if the market presents a greater demand to our supply capacity and be justified by cost / benefit ratio, the entry into this market through a joint venture or subsidiary is that the decision will be taken. Although this is a case study, which means that is adjusted to the concrete case Tubofuro® preventing generalization of findings, we believe that this work can be a useful example for other companies in the internationalization process or the methodology adopted in formulating strategy or the outputs and conclusions drawn.

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Introduction The concept of this thesis was driven by stagnation within the Irish healthcare system. Multiple reports from pharmacy organisations had outlined possible future directions for the profession but progress was minimal, especially in comparison with other countries. The author’s directive was to evaluate the economic impact of a series of clinical pharmacy services (CPS) in hospital and community settings. Methods A systematic review of economic evaluations of clinical pharmacy services in hospital patients was undertaken to gain insight into recent research in the field. Eligible studies were evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), to establish the quality, consistency and transparency of relevant research. A retrospective analysis of an internal hospital pharmacy interventions database was conducted. A method first described by Nesbit et al. was implemented to estimate the level of cost avoidance achieved. A cost-effectiveness analysis based on data from a randomised controlled trial of a pharmacist-supervised patient self-testing (PST) of warfarin therapy is presented. Outcome measure was the incremental cost associated with six months of intervention management. A similar cost-effectiveness analysis based on previously published RCT data was used to evaluate a novel structured pharmacist review of medication in older hospitalised patients. Cost-effectiveness analysis was presented in the form of an incremental cost-effectiveness ratio (ICER). An ICER is an additional cost per unit effect, in the case of this study, the cost of preventing an additional non-trivial ADR in hospital. A method described by Preaud et al. was adapted to estimate the clinical and economic benefit gained from vaccination of patients by a community pharmacist in Ireland in 2013/14. Sample demographic data was obtained from a national chain of community pharmacies and applied to overall national vaccination data. Results Systematic review identified twenty studies which were eligible for inclusion. Overall, pharmacist interventions had a positive impact on hospital budgets. Only three studies (15%) were deemed to be “good-quality” studies. No ‘novel’ clinical pharmacist intervention was identified during the course of this review. Analysis of internal hospital database identified 4,257 interventions documented on 2,147 individual patients over a 12 month period. Substantial cost avoidance of €710,000 was generated over a 1 year period from the perspective of the health care provider. Mean cost avoidance of €166 per intervention was generated. The cost of providing these interventions was €82,000. Substantial net cost-benefits of €626,279 and a cost-benefit ratio of 8.64 : 1 were generated based on this evaluation of pharmacist interventions. Results from an evaluation of a novel pharmacist-led form of warfarin management indicated indicated that on a per patient basis, PST was slightly more expensive than established anticoagulant management. On a per patient basis over a six month period, PST resulted in an incremental cost of €59.08 in comparison with routine care. Overall cost of managing a patient through pharmacist-supervised PST for a six month period is €226.45. However, for this increase in cost a clinically significant improvement in care was provided. Patients achieved a significantly higher time in therapeutic range during the PST arm in comparison with routine care, (72 ± 19.7% vs 59 ± 13.5%). Difference in overall cost was minimal and PST was the dominant strategy in some scenarios examined during sensitivity analysis. Structured pharmacist review of medication was determined to be dominant in comparison to usual pharmaceutical care. Even if the healthcare payer was unwilling to pay any money for the prevention of an ADR, the intervention strategy is still likely to be cost-effective (probability of being determined cost-effective = 0.707). Implementation of pharmacist-led influenza vaccination has resulted in substantial clinical and economic benefits to the healthcare system. The majority of patients (64.9%) who availed of this service had identifiable influenza-related risk factors. Of patients with influenza-related risk factors, age ≥65 year was the most commonly cited risk factor. Pharmacist vaccination services averted a total of 848 influenza cases across all age groups during the 2013/2014 influenza season. Due to receipt of vaccination in a pharmacy setting, 444 influenza-related GP visits were prevented. In terms of more serious influenza-associated events, 11 hospitalisations and five influenza-related deaths were averted. Costs averted were approximately €305,000. These were principally wider societal-related costs associated with lost productivity. Conclusion Overall, clinical pharmacy services are adding value to the Irish healthcare system in both hospital and community settings, but provision of additional funding for new services would enable them to offer a great deal more.

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Introduccion: El canal lumbar estrecho es un motivo de consulta frecuente en el servicio de columna de la Fundación Santa Fe de Bogotá. Derivado del tratamiento quirurgico se pueden generar múltiples complicaciones, entre las que se encuentra la transfusión sanguínea. Objetivo: Identificar los factores sociodemográficos, antecedentes personales y factores quirúrgicos asociados a transfusión sanguínea en cirugía canal lumbar estrecho en la Fundación Santa Fe de Bogotá 2003- 2013. Materiales y métodos: Se aplicó en diseño de estudio observacional analítico transversal. Se incluyeron 367 pacientes sometidos a cirugía de canal lumbar estrecho a quienes se les analizaron variables de antecedentes personales, características sociodemograficas y factores quirúrgicos. Resultados: La mediana de la edad fue de 57 años y la mayoría de pacientes fueron mujeres (55,6%). La mediana del Índice de Masa Corporal (IMC) fue de 24,9 clasificado como normal. Entre los antecedentes patológicos, la hipertensión arterial fue el más común (37,3%). La mayoría de pacientes (59,1%) presentaron clasificación ASA de II. El tipo de cirugía más prevalente fue el de descompresión (55,6%). En el 79,8% de los pacientes se intervinieron 2 niveles. Se realizó transfusión de glóbulos rojos en 26 pacientes correspondiente a 7,1% del total. En la mayoría de procedimientos quirúrgicos (42,5%) el sangrado fue clasificado como moderado (50-500 ml). En el modelo explicativo transfusión sanguínea en cirugía de canal lumbar estrecho se incluyen: antecedente de cardiopatía (OR 4,68, P 0,034, IC 1,12 – 19,44), Sangrado intraoperatorio >500ml (OR 6,74, p 0,001, 2,09 – 21,74) y >2 niveles intervenidos (OR 3,97, p 0,023, IC 1,20 – 13,09). Conclusión: Como factores asociados a la transfusión sanguínea en el manejo quirúrgico del canal lumbar estrecho a partir de la experiencia de 10 años en la Fundación Santa Fe de Bogotá se encontraron: enfermedad cardiaca, sangrado intraoperatorio mayor de 500ml y más de dos niveles intervenidos.

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his report describes in detail a project aimed at providing a better understanding of the business drivers and barriers to the adoption of Building Information Modelling (BIM) in the Architecture Engineering and Construction (AEC) and facility management (FM) industry sectors. The objectives of the project were to investigate the nature of economic, process and industry constraints to BIM adoption and then - if possible - to identify business strategies, and cost/benefit models that may support adoption of BIM in AEC/FM industry. The research was based on case studies from the property, construction and facility management sectors as well as other industries and interviews with business leaders and users of advanced applications of CAD in the industry.

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Background Colorectal cancer survivors may suffer from a range of ongoing psychosocial and physical problems that negatively impact on quality of life. This paper presents the study protocol for a novel telephone-delivered intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors. Methods/Design Approximately 350 recently diagnosed colorectal cancer survivors will be recruited through the Queensland Cancer Registry and randomised to the intervention or control condition. The intervention focuses on symptom management, lifestyle and psychosocial support to assist participants to make improvements in lifestyle factors (physical activity, healthy diet, weight management, and smoking cessation) and health outcomes. Participants will receive up to 11 telephone-delivered sessions over a 6 month period from a qualified health professional or 'health coach'. Data collection will occur at baseline (Time 1), post-intervention or six months follow-up (Time 2), and at 12 months follow-up for longer term effects (Time 3). Primary outcome measures will include physical activity, cancer-related fatigue and quality of life. A cost-effective analysis of the costs and outcomes for survivors in the intervention and control conditions will be conducted from the perspective of health care costs to the government. Discussion The study will provide valuable information about an innovative intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors.

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Since the 1960s, the value relevance of accounting information has been an important topic in accounting research. The value relevance research provides evidence as to whether accounting numbers relate to corporate value in a predicted manner (Beaver, 2002). Such research is not only important for investors but also provides useful insights into accounting reporting effectiveness for standard setters and other users. Both the quality of accounting standards used and the effectiveness associated with implementing these standards are fundamental prerequisites for high value relevance (Hellstrom, 2006). However, while the literature comprehensively documents the value relevance of accounting information in developed markets, little attention has been given to emerging markets where the quality of accounting standards and their enforcement are questionable. Moreover, there is currently no known research that explores the association between level of compliance with International Financial Reporting Standards (IFRS) and the value relevance of accounting information. Motivated by the lack of research on the value relevance of accounting information in emerging markets and the unique institutional setting in Kuwait, this study has three objectives. First, it investigates the extent of compliance with IFRS with respect to firms listed on the Kuwait Stock Exchange (KSE). Second, it examines the value relevance of accounting information produced by KSE-listed firms over the 1995 to 2006 period. The third objective links the first two and explores the association between the level of compliance with IFRS and the value relevance of accounting information to market participants. Since it is among the first countries to adopt IFRS, Kuwait provides an ideal setting in which to explore these objectives. In addition, the Kuwaiti accounting environment provides an interesting regulatory context in which each KSE-listed firm is required to appoint at least two external auditors from separate auditing firms. Based on the research objectives, five research questions (RQs) are addressed. RQ1 and RQ2 aim to determine the extent to which KSE-listed firms comply with IFRS and factors contributing to variations in compliance levels. These factors include firm attributes (firm age, leverage, size, profitability, liquidity), the number of brand name (Big-4) auditing firms auditing a firm’s financial statements, and industry categorization. RQ3 and RQ4 address the value relevance of IFRS-based financial statements to investors. RQ5 addresses whether the level of compliance with IFRS contributes to the value relevance of accounting information provided to investors. Based on the potential improvement in value relevance from adopting and complying with IFRS, it is predicted that the higher the level of compliance with IFRS, the greater the value relevance of book values and earnings. The research design of the study consists of two parts. First, in accordance with prior disclosure research, the level of compliance with mandatory IFRS is examined using a disclosure index. Second, the value relevance of financial statement information, specifically, earnings and book value, is examined empirically using two valuation models: price and returns models. The combined empirical evidence that results from the application of both models provides comprehensive insights into value relevance of accounting information in an emerging market setting. Consistent with expectations, the results show the average level of compliance with IFRS mandatory disclosures for all KSE-listed firms in 2006 was 72.6 percent; thus, indicating KSE-listed firms generally did not fully comply with all requirements. Significant variations in the extent of compliance are observed among firms and across accounting standards. As predicted, older, highly leveraged, larger, and profitable KSE-listed firms are more likely to comply with IFRS required disclosures. Interestingly, significant differences in the level of compliance are observed across the three possible auditor combinations of two Big-4, two non-Big 4, and mixed audit firm types. The results for the price and returns models provide evidence that earnings and book values are significant factors in the valuation of KSE-listed firms during the 1995 to 2006 period. However, the results show that the value relevance of earnings and book values decreased significantly during that period, suggesting that investors rely less on financial statements, possibly due to the increase in the available non-financial statement sources. Notwithstanding this decline, a significant association is observed between the level of compliance with IFRS and the value relevance of earnings and book value to KSE investors. The findings make several important contributions. First, they raise concerns about the effectiveness of the regulatory body that oversees compliance with IFRS in Kuwait. Second, they challenge the effectiveness of the two-auditor requirement in promoting compliance with regulations as well as the associated cost-benefit of this requirement for firms. Third, they provide the first known empirical evidence linking the level of IFRS compliance with the value relevance of financial statement information. Finally, the findings are relevant for standard setters and for their current review of KSE regulations. In particular, they highlight the importance of establishing and maintaining adequate monitoring and enforcement mechanisms to ensure compliance with accounting standards. In addition, the finding that stricter compliance with IFRS improves the value relevance of accounting information highlights the importance of full compliance with IFRS and not just mere adoption.