Management of patients with elevated Self-BAT scores or other bleeding symptoms: Updated overview for primary care practitioners.

OBJECTIVE: To provide recommendations for management of patients presenting with elevated self-administered bleeding assessment tool (Self-BAT) scores or other bleeding symptoms in a primary care setting. SOURCES OF INFORMATION: Primary research sources, clinical review articles, and interviews with research staff, hematologists, and family physicians were used to create the poster tools and reference guide resources. MAIN MESSAGE: Recommendations to manage a patient with an elevated Self-BAT score or other bleeding symptoms include reviewing the results of the Self-BAT to clarify relevant symptoms, performing initial diagnostic laboratory tests, and doing basic symptom management. Clinical judgment should be used when determining whether referral to a hematologist is necessary, but referral should be considered if the bleeding score is abnormal or if initial management options are ineffective. Some bleeding symptoms warrant evaluation by a gastroenterologist, obstetrician-gynecologist, or otolaryngologist. CONCLUSION: Primary care providers should conduct a thorough review of the Self-BAT results and associated management recommendations when working with a patient presenting with an elevated score or other bleeding manifestations. A review consists of the clarification of relevant symptoms, appropriate initial laboratory workups, and patient education. Treatment options for symptom management should be explored while recognizing the threshold for referral to a hematologist.

Cardiovascular Risk Screening and Pregnancy Complications: A Comparison of Two Canadian Maternal Health Clinic Populations.

OBJECTIVE: This study compared pregnancy-related cardiovascular disease risk indicators between women who attended 2 different postpartum screening and education clinics: 1 at an urban tertiary care centre and 1 at a northern, rural community hospital. Risk differences associated with ethnicity were also examined. METHODS: We conducted a retrospective record review that compared data from an urban clinic in Kingston, Ontario (n = 675) with those from a rural clinic in Prince Rupert, British Columbia (n = 65). Patients who had a hypertensive disorder of pregnancy, gestational diabetes, intrauterine growth restriction, idiopathic preterm birth, or placental abruption attended the clinics at 6 months postpartum. Demographic information, personal and family history, physical examination findings, and laboratory results were collected and used to generate cardiovascular risk estimates using validated scoring systems. These estimates were compared between clinic populations and between ethnic subsets. RESULTS: Fifty-five percent of the Prince Rupert cohort were Indigenous, while 87% of the Kingston cohort were White (P < 0.001). A greater proportion of the Kingston cohort had experienced hypertensive disorders of pregnancy (P = 0.002), while a greater proportion of the Prince Rupert cohort had developed gestational diabetes (P=0.010). The Prince Rupert population had higher lifetime and 30-year cardiovascular disease risk scores (P = 0.008 and P = 0.005, respectively). Indigenous patients had more major cardiovascular risk factors as well as higher lifetime and 30-year cardiovascular risk scores (P = 0.001 and P = 0.008, respectively) than White and Asian patients. CONCLUSION: The increased cardiovascular disease risk in both rural and Indigenous women supports the need for better postpartum care, long-term follow-up, and early promotion of cardiovascular health in these populations.

Exploring the nausea experience among female patients with breast cancer; A pilot interview study.

INTRODUCTION: Nausea is a difficult symptom to report and measure in clinical trials. We conducted a pilot interview study to improve our understanding of the nausea experience. MATERIALS AND METHODS: Female patients with breast cancer that had experienced nausea during radiation therapy and/or chemotherapy underwent semi-structured interviews that focused on patient-defined and standard definitions, preferences for nausea grading scales, and nausea sub-features: intensity, location, timing/duration, character, associated symptoms, precipitating/alleviating factors, impact on quality of life. RESULTS: 10 patients were interviewed. Patients defined nausea more variably than vomiting and retching/dry heaving. An ordinal grading scale with a 0-10 intensity range was preferred over visual-analogue and qualitative scales. Patients had experienced different intensities of nausea and deemed reporting their worst, average and least intensities feasible. High-intensity episodes were deemed more problematic than low-intensity episodes regardless of their duration. The duration and character of nausea were difficult to describe. A range of associated symptoms, precipitating and alleviating factors were documented. Nausea had a detrimental impact on quality of life. CONCLUSIONS: Nausea has a range of subjective and objective features. Our pilot study provided valuable information that will inform the design of a planned larger survey study. Creating an operational clinical trial definition for nausea appears feasible.

Phenytoin Toxicity During Neoadjuvant Concurrent Capecitabine and Radiation Therapy for Rectal Adenocarcinoma: Case Report of a Drug Interaction.

Phenytoin toxicity occurs when serum levels exceed the therapeutic level, leading to symptoms such as nystagmus, slurred speech, and decreased coordination. This toxicity is sometimes caused by drug interactions. Interactions between phenytoin and capecitabine are not commonly documented. We report the case of a 52-year-old man taking phenytoin for atypical meningioma who developed symptoms of phenytoin toxicity while receiving capecitabine in the treatment of rectal adenocarcinoma.

Malignant Gastric Outlet Obstruction from Pancreatic Cancer.

Patients with advanced-stage pancreatic cancer are typically burdened by many symptoms that impair functioning and worsen quality of life. We report an exceptional case of a 73-year-old woman with T4N1M0 adenocarcinoma of the uncinate process of the pancreas who developed significant gastric outlet obstruction - an uncommon yet potentially life-threatening complication of disease progression. She developed progressive abdominal pain and emesis, and profound dilatation of her stomach was detected on a radiation therapy simulation CT scan that required urgent decompression. Malignant gastric outlet obstruction must be included in the differential diagnosis when patients with known advanced disease of the pancreas present with obstructive upper gastrointestinal symptoms.

Palliative Radiation Therapy for Symptom Control in an Advanced Case of Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PP) is a rare clinical condition characterized by progressive mucinous ascites, which is typically caused by a mucin-producing neoplasm. Reports of radiation therapy (RT) in the management of PP are limited. We report a unique case of a 62-year-old woman with severe, end-stage, recurrent PP and a large, mucin-secreting mass protruding through her abdominal wall. Low-dose, hypofractionated palliative RT was administered for symptom control with the hope of improving her quality of life. We suggest that radiation therapy be considered in the comprehensive palliative management of patients with PP.

A systematic review of methodologies, endpoints, and outcome measures in randomized trials of radiation therapy-induced nausea and vomiting.

PURPOSE: Clinical trials in radiation therapy-induced nausea and vomiting (RINV) appear to have varied methodologies, endpoints, and outcome measures. This complicates trial comparisons, weakens practice guideline recommendations, and contributes to variability in supportive care patterns of practice. We systematically reviewed RINV trials to describe and compare their pertinent design features. MATERIALS AND METHODS: Ovid versions of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE to January/February 2017 were searched for adult phase III trials of RINV management strategies. Key abstracted data included trial interventions and eligibility criteria, standard radiation therapy (RT) metrics, symptom assessment procedures, symptom definitions and grading systems, pre-specified and reported endpoints, and other outcome measures. RESULTS: From 1166 references identified in the initial database search, we selected 34 trials for analysis that collectively randomized 4529 patients (median 61, range 11-1492). Twenty-eight trials (82%) were published prior to the year 2000. Twenty-seven trials (79%) involved multiple fraction RT and 7 (21%) single fraction RT. Twenty-four trials (71%) evaluated prophylactic interventions, 9 (26%) rescue interventions, and 1 trial did not specify. Thirty-three trials (97%) evaluated pharmacologic interventions. Twenty trials (59%) had patient report symptoms, 5 (15%) healthcare professionals or researchers, and 10 (29%) did not specify. Nausea was not defined in any trial but was reported as a stand-alone symptom in 26 trials (76%) and was graded in 20 (59%), with categorical qualitative scales being the most common method. Vomiting was defined in 3 trials (9%), was reported as a stand-alone symptom in 17 (47%), and was graded in 7 (21%), with continuous numerical scales being the most common method. Retching was defined in 3 trials, was not reported as a stand-alone symptom in any trial, and was graded in 1 (3%). Twenty-one trials (62%) created compound symptom measures that combined individual symptoms. Fifteen trials (44%) reported "emetic episode/event" measures but only 9 defined them. Seventeen trials (50%) reported complicated endpoints (e.g., "response," "control," "success") that combined multiple symptom or compound symptom measures, but 7 did not define them comprehensively. Ten trials (29%) defined a primary endpoint a priori. CONCLUSIONS: Methodologies, endpoints, and outcome measures varied considerably among 34 randomized trials in RINV.

RELATIVE EFFECTIVENESS IN BREAST CANCER TREATMENT: A HEALTH PRODUCTION APPROACH.

BACKGROUND: Pharmaceuticals' relative effectiveness has come to the fore in the policy arena, reflecting the need to understand how relative efficacy (what can work) translates into added benefit in routine clinical use (what does work). European payers and licensing authorities assess value for money and post-launch benefit-risk profiles, and efforts to standardize assessments of relative effectiveness across the European Union (EU) are under way. However, the ways that relative effectiveness differs across EU healthcare settings are poorly understood. METHODS: To understand which factors influence differences in relative effectiveness, we developed an analytical framework that treats the healthcare system as a health production function. Using evidence on breast cancer from England, Spain, and Sweden as a case study, we investigated the reasons why the relative effectiveness of a new drug might vary across healthcare systems. Evidence was identified from a literature review and national clinical guidance. RESULTS: The review included thirteen international studies and thirty country-specific studies. Cross-country differences in population age structure, deprivation, and educational attainment were consistently associated with variation in outcomes. Screening intensity appeared to drive differences in survival, although the impact on mortality was unclear. CONCLUSIONS: The way efficacy translates into relative effectiveness across health systems is likely to be influenced by a range of complex and interrelated factors. These factors could inform government and payer policy decisions on ways to optimize relative effectiveness, and help increase understanding of the potential transferability of data on relative effectiveness from one health system to another.

UNDERSTANDING VARIATIONS IN RELATIVE EFFECTIVENESS: A HEALTH PRODUCTION APPROACH.

BACKGROUND: Relative effectiveness has become a key concern of health policy. In Europe, this is because of the need for early information to guide reimbursement and funding decisions about new medical technologies. However, ways that effectiveness (does it work?) and efficacy (can it work?) might differ across health systems are poorly understood. METHODS: This study proposes an analytical framework, drawing on production function theory, to systematically identify and quantify the determinants of relative effectiveness and sources of variation between populations and healthcare systems. We consider how methods such as stochastic frontier analysis and data envelopment analysis using a Malmquist productivity index could in principle be used to generate evidence on, and improve understanding about, the sources of variation in relative effectiveness between countries and over time. RESULTS: Better evidence on factors driving relative effectiveness could: inform decisions on how to best use a new technology to maximum effectiveness; establish the need if any for follow-up post-launch studies, and provide evidence of the impact of new health technologies on outcomes in different healthcare systems. CONCLUSIONS: The health production function approach for assessment of relative effectiveness is complementary to traditional experimental and observational studies, focusing on identifying, collecting, and analyzing data at the national level, enabling comparisons to take place. There is a strong case for exploring the use of this approach to better understand the impact of new medicines and devices for improvements in health outcomes.

Distribution of health-related social surplus in pharmaceuticals: an estimation of consumer and producer surplus in the management of high blood lipids and COPD.

BACKGROUND: Following suggestions that developers should be allowed to capture a defined share of the total value generated by their technologies, the amount of surplus accruing to the pharmaceutical industry has become an important concept when discussing policies to encourage innovation in healthcare. METHODS: Observational clinical and market data spanning over a period of 20 years were applied in order to estimate the social surplus generated by pharmaceuticals used in the management of high cholesterol and chronic obstructive pulmonary disease (COPD). The distribution of social surplus between consumers and producers was also computed and the dynamics of rent extraction examined. RESULTS: Health-related social surplus increased consistently over time for both disease areas, mostly due to the launch of more effective technologies and a greater number of patients being treated for the conditions. However, the growth rate of social surplus differed for each disease and dissimilar patterns of distribution between consumer and producer surplus emerged across the years. For lipid-lowering therapies, yearly consumer surplus reaches 85 % of total health-related social surplus after the loss of exclusivity of major molecules, whilst for COPD it ranges from 54 to 69 %. Average producer surplus is approximately 25 % of total health-related social surplus in the lipid-lowering market between 1990 and 2010, and 37 % for COPD between 2001 and 2010. The share of surplus captured by non-innovative generic producers also varies differently across periods for both markets, reaching 11.12 % in the case of lipid-lowering therapies but just 1.55 % in the case of COPD. CONCLUSION: A considerable amount of the value may be recouped by consumers only towards the end of the lifecycle. Elements affecting the distribution of social surplus vary across disease areas and include the market pricing structure and the pattern of clinical effectiveness observed over time. The application of a longer-term disease specific perspective may be required when assessing the cost-effectiveness of health technologies at launch.

The determinants of cost-effectiveness potential: an historical perspective on lipid-lowering therapies.

BACKGROUND: The concept of cost effectiveness emerged in an attempt to link the prices of new healthcare technologies to the immediate value they provide, with payers defining the acceptable cost per unit of incremental effect over the alternatives available. It has been suggested that such measures allow developers to assess potential market profitability in an early stage of development, but may result in discouraging investment in efficient research if not used appropriately. OBJECTIVE: The objective of this study is to identify the pattern of the factors determining cost effectiveness and assess the evolution of cost-effectiveness potential for drugs in development using lipid-lowering therapy as a case study. METHODS: The study is based on observational clinical and market data covering a 20-year period (from 1990 to 2010) in the UK. Real-life clinical data including total cholesterol laboratory test results were extracted from the Clinical Practice Research Datalink (CPRD) and are used to illustrate how the clinical effectiveness of existing standard care changed over time in patients managed in clinical practice. Prescription Cost Analysis (PCA) data were extracted and the average price of the drug mix used was computed throughout the study period. Using this information, the maximum clinical benefit and cost savings to be had were estimated for each year of the analysis using a cost-effectiveness model. Subsequently, the highest price a new technology providing the maximum clinical effectiveness possible (i.e. eliminating cardiovascular risk from high cholesterol levels) could achieve under current cost-effectiveness rules was calculated and used as a measure of the potential cost effectiveness of drugs in development. RESULTS: The results in this study show that the total cholesterol values of patients managed in clinical practice moved steadily towards recommended clinical targets. Overall, the absolute potential for incremental health-related quality of life decreased by approximately 78 %, contracting from 0.36 QALYs to 0.08 QALYs, which resulted in a saving of approximately 15 % of the costs related to cardiovascular events. The price of the drug mix used in the management of high blood cholesterol varied considerably across the years: the weighted average monthly price (in year 2007 values) started at approximately £14, peaked around £26 and progressively decreased to its minimum at £6.85 in 2010. As a consequence, the maximum price allowed by current cost-effectiveness rules for a new technology achieving the clinical target was found to decrease by a minimum of 80 % between 1990 and 2010. CONCLUSION: The analysis supports the hypothesis that the potential for cost effectiveness of new therapies is dependent on factors specific to each disease area and furthermore to sub-populations within disease areas. Despite a clinical need still existing, the results suggest that no more technologies are likely to be developed in certain disease areas based on their low perceived cost-effectiveness potential. This occurs without considering the immediate and future value of the effectiveness lost, which may depend on the technical difficulty of materializing future advancements, and ignores the permanent character of such a decision. The analysis suggests that a single, static and arbitrary cost-effectiveness threshold may not be sufficient to capture the drug-development dynamics occurring at the disease level and successfully direct research to the disease areas that are most valued by society.

Assessing the determinants of the potential for cost-effectiveness over time: the empirical case of COPD.

OBJECTIVES: The objective of this study was to assess the potential for cost-effectiveness of new technologies for chronic obstructive pulmonary disease (COPD) over the period from 2001 to 2010. METHODS: Lung function outcomes and drug prices were observed for a UK COPD population over the period from 2001 to 2010. Cost-effectiveness was assessed at regular intervals on the basis of an established cost-effectiveness model, and the maximum price a technology providing cure could achieve under the current cost-effectiveness rules was estimated. RESULTS: The results of this study show that although the scope for clinical improvement in COPD was still considerable, during the 10 years studied, the potential for cost-effectiveness at each point in time was dependent on momentary market characteristics, such as the changing price of comparators and improvements in clinical effectiveness. As a result, the analysis demonstrates that the future cost-effectiveness of a technology in development depends on the manner pricing and clinical effectiveness evolve throughout time. CONCLUSIONS: Because any predictions will be short-lived and dependent on a number of uncertain factors, we conclude that producing accurate forecasts on the potential for cost-effectiveness of new therapies earlier during the development process is especially difficult under the current static cost-effectiveness framework.

A comparison of pharmaceutical reimbursement agencies' processes and methods in France and Scotland.

OBJECTIVES: Pharmaceutical reimbursement agencies' processes and methods of appraisal vary across countries. The objective of this study was to examine the contribution of formal health economic analysis in a process using such analysis in Scotland in comparison to a process not routinely using such analysis in France. METHODS: A framework for classifying reimbursement systems was used to analyze the two systems. A typology of recommendation was defined and a qualitative analysis of decisions on a sample of medicines appraised by both reimbursement agencies was conducted. Reasons for differences in recommendations were analyzed and case studies selected to illustrate the common reasons. RESULTS: Thirty-nine common medicines appraised by both agencies were identified between 2005 and 2010, treating a variety of diseases for which the Scottish Medicines Consortium tended to provide more restrictive, or did not recommend, listing. Similarities in clinical evidence submitted to the respective reimbursement committees were observed. Differences in recommendation can be explained by a combination of the manufacturer's freedom to set price and the incentives provided by the consideration of health economic analysis and quality of life, alongside differences in relevant comparators, relevant outcomes, treatment guidelines, and the propensity to use network meta-analysis, in decision making. CONCLUSIONS: This study provides some explanations and hypotheses for the differences observed in recommendations for a selected sample of medicines with regards to differences in appraisal processes and methods adopted. Further research using larger datasets may allow stakeholders to assess the impact of such differences on the efficient use of health resources.

Antihypertensive drugs: a perspective on pharmaceutical price erosion and its impact on cost-effectiveness.

OBJECTIVE: When comparators' prices decrease due to market competition and loss of exclusivity, the incremental clinical effectiveness required for a new technology to be cost-effective is expected to increase; and/or the minimum price at which it will be funded will tend to decrease. This may be, however, either unattainable physiologically or financially unviable for drug development. The objective of this study is to provide an empirical basis for this discussion by estimating the potential for price decreases to impact on the cost-effectiveness of new therapies in hypertension. METHODS: Cost-effectiveness at launch was estimated for all antihypertensive drugs launched between 1998 and 2008 in the United Kingdom using hypothetical degrees of incremental clinical effectiveness within the methodologic framework applied by the UK National Institute for Health and Clinical Excellence. Incremental cost-effectiveness ratios were computed and compared with funding thresholds. In addition, the levels of incremental clinical effectiveness required to achieve specific cost-effectiveness thresholds at given prices were estimated. RESULTS: Significant price decreases were observed for existing drugs. This was shown to markedly affect cost-effectiveness of technologies entering the market. The required incremental clinical effectiveness was in many cases greater than physiologically possible so, as a consequence, a number of products might not be available today if current methods of economic appraisal had been applied. CONCLUSIONS: We conclude that the definition of cost-effectiveness thresholds is fundamental in promoting efficient innovation. Our findings demonstrate that comparator price attrition has the potential to put pressure in the pharmaceutical research model and presents a challenge to new therapies being accepted for funding.

A dynamic perspective on pharmaceutical competition, drug development and cost effectiveness.

Limited healthcare budgets result in payers adopting policies at national, regional or local level to achieve allocative efficiency in drug spending. Some of these aim at creating a link between pharmaceutical prices and the value they provide by setting a cost effectiveness (CE) threshold as the maximum acceptable ratio between incremental costs and effects of new drugs. The clinical effectiveness of the comparator used in those CE analyses tends to be greater over time, whilst, due to market competition and loss of exclusivity, their price is expected to be lower. At the same time, research and development (R&D) costs increase with inflation and with efforts to address regulation towards increased safety concerns. As effective patent times decrease, a minimum price constraint raises for the new entrant. These features occur at different rates across disease areas and are expected to result in differently shaped innovation curves. In this scenario, we demonstrate that a general arbitrary threshold may prevent further efficient R&D. Investment may be withdrawn before the optimum innovation point is reached and affordable clinical effectiveness may be lost. We conclude that disease-specific characteristics are an additional consideration in CE decision rules to accommodate the particularities of innovation across disease areas.

Using qualitative methods to inform the trade-off between content validity and consistency in utility assessment: the example of type 2 diabetes and Alzheimer's disease.

BACKGROUND: Key stakeholders regard generic utility instruments as suitable tools to inform health technology assessment decision-making regarding allocation of resources across competing interventions. These instruments require a 'descriptor', a 'valuation' and a 'perspective' of the economic evaluation. There are various approaches that can be taken for each of these, offering a potential lack of consistency between instruments (a basic requirement for comparisons across diseases). The 'reference method' has been proposed as a way to address the limitations of the Quality-Adjusted Life Year (QALY). However, the degree to which generic measures can assess patients' specific experiences with their disease would remain unresolved. This has been neglected in the discussions on methods development and its impact on the QALY values obtained and resulting cost per QALY estimate underestimated. This study explored the content of utility instruments relevant to type 2 diabetes and Alzheimer's disease (AD) as examples, and the role of qualitative research in informing the trade-off between content coverage and consistency. METHOD: A literature review was performed to identify qualitative and quantitative studies regarding patients' experiences with type 2 diabetes or AD, and associated treatments. Conceptual models for each indication were developed. Generic- and disease-specific instruments were mapped to the conceptual models. RESULTS: Findings showed that published descriptions of relevant concepts important to patients with type 2 diabetes or AD are available for consideration in deciding on the most comprehensive approach to utility assessment. While the 15-dimensional health related quality of life measure (15D) seemed the most comprehensive measure for both diseases, the Health Utilities Index 3 (HUI 3) seemed to have the least coverage for type 2 diabetes and the EuroQol-5 Dimensions (EQ-5D) for AD. Furthermore, some of the utility instruments contained items that could not be mapped onto either of the proposed conceptual models. CONCLUSIONS: Content of the utility measure has a significant impact on the treatment effects that can be observed. This varies from one disease to the next and as such contributes to lack of consistency in observable utility effects and incremental utility scores. This observation appears to have been omitted from the method development considerations such as reference methods. As a result, we recommend that patients' perspectives obtained via qualitative methods are taken into consideration in the ongoing methods development in health state descriptions for generic utility instruments. Also, as a more immediate contribution to improving decision making, we propose that a content map of the chosen utility measure with patient-reported domains be provided as standard reporting in utility measurement in order to improve the transparency of the trade-offs in relation to patient relevance and consistency.

Framework for describing and classifying decision-making systems using technology assessment to determine the reimbursement of health technologies (fourth hurdle systems).

OBJECTIVES: Australia, Canada, and many European countries now use various forms of health technology assessment (HTA) in decision making regarding the reimbursement of drugs and other health technologies. To achieve a better understanding of the potential for use of HTA in this context, an analytical framework was developed to describe and classify existing fourth hurdle systems. METHODS: Based on a review of published literature, and official documentation, the key aspects of a fourth hurdle system were identified at two levels: policy implementation and individual technology decision. Characteristics of the systems were grouped under four main headings: constitution and governance, objectives, use of evidence and decision processes, and accountability. The comprehensiveness and relevance of this framework was assessed by an independent group of experts in HTA. A pilot study was undertaken, using only published sources, to test the feasibility of obtaining the information needed to complete the framework. RESULTS: The framework was found to be sufficiently broad to encompass all the issues of interest regarding the systems, but the proportion of information available from published sources was variable between sections of the framework and between countries, with average availability of 45 percent. CONCLUSIONS: The analytical framework will help researchers and policy makers in individual countries to understand their own systems and will allow some preliminary sharing of experience between countries. More experience of its application is needed to judge whether it will provide the basis for more formal comparison of systems and whether it will determine their appropriateness for particular decision contexts.