A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

A multicenter chart review of patient characteristics, treatment, and outcomes in hereditary angioedema: unmet need for more effective long-term prophylaxis.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurring subcutaneous or submucosal swelling. Without effective therapy, HAE can negatively impact patients' quality of life. Management of HAE includes on-demand treatment of attacks and short- and long-term prophylaxis (LTP) to prevent attacks. Newer therapies may be more tolerable and effective in managing HAE; however, therapies such as androgens are still widely used in some countries owing to their relative ease of access and adequate disease control for some patients. This study evaluated the characteristics, treatment patterns, clinical outcomes, and healthcare resource utilization of a multinational cohort of patients with HAE, with a focus on understanding reasons for recommending or discontinuing available therapies. METHODS: A retrospective chart review was conducted at 12 centers in six countries and included data from patients with HAE type 1 or 2 who were ≥ 12 years of age at their first clinical visit. The relationship between LTP use and attack rates was evaluated using a multivariable Poisson regression model. Data were collected between March 2018 and July 2019. RESULTS: Data from 225 patients were collected (62.7% female, 86.2% White, 90.2% type 1); 64.4% of patients had their first HAE-related visit to the center prior to or during 2014. Treatment patterns varied between countries. Overall, 85.8% of patients were prescribed on-demand treatment and 53.8% were prescribed LTP, most commonly the androgen danazol (53.7% of patients who used LTP). Plasma-derived C1 inhibitor (Cinryze®) was used by 29.8% of patients for LTP. Patients who received LTP had a significantly lower rate of HAE attacks than patients who did not receive any LTP (incidence rate ratio (95% confidence interval) 0.90 (0.84-0.96)). Androgens were the most commonly discontinued therapy (51.3%), with low tolerability cited as the most frequent reason for discontinuation (50.0%). CONCLUSIONS: Overall, findings from this study support the use of LTP in the prevention of HAE attacks; a lower rate of attacks was observed with LTP compared with no LTP. However, the type of LTP used varied between countries, with tolerability and accessibility to specific treatments playing important roles in management decision-making.

Content validation and psychometric evaluation of the Angioedema Quality of Life Questionnaire for hereditary angioedema.

BACKGROUND: There is considerable burden of illness in hereditary angioedema (HAE). However, instruments to assess health-related quality of life (HRQoL) in HAE are limited. The Angioedema Quality of Life Questionnaire (AE-QoL) was developed to measure HRQoL in patients with recurrent angioedema; the validity of the AE-QoL in patients with HAE is described. METHODS: To identify disease-related experiences with a focus on the impact of HAE on HRQoL, interviews were conducted with a group of clinician experts and patients with HAE from Canada, France, Germany, Spain, the United Kingdom, and the United States, along with a targeted literature review. Concepts were mapped to the AE-QoL to assess item relevance, interpretation, and conceptual coverage. Cognitive interviews assessed item clarity and relevance. A psychometric validation was performed using data from a phase 3 trial. RESULTS: Interviews were conducted with seven clinicians and 40 adult patients. Patients reported 35 unique impacts of HAE on their lives, the most frequent being on work/school, social relationships, physical activities, and emotions, particularly fear/worrying and anxiety. Saturation for these impacts was reached, and all concepts covered in the AE-QoL were reported during the interviews. Patients agreed that the questionnaire items and response options were clear and relevant, and the 4-week recall period was appropriate. The psychometric validation included data from 64 patients. For AE-QoL total scores, excellent internal consistency (Cronbach's alpha > 0.90), test-retest reliability (intraclass coefficient > 0.80), convergent validity with the Sheehan Disability Scale (r = 0.663), divergent validity with the EQ-5D-5L index (r = 0.292) and EQ-VAS (r = 0.337), and known-groups validity (p < 0.0001; ɳ2 = 0.56) were demonstrated. CONCLUSIONS: Qualitative and psychometric analyses showed that the AE-QoL is a reliable and valid instrument for measuring HRQoL in adult patients with HAE from six countries.

Indirect Comparison of Lanadelumab and Intravenous C1-INH Using Data from the HELP and CHANGE Studies: Bayesian and Frequentist Analyses.

BACKGROUND: Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is a rare disease associated with painful, potentially fatal swelling episodes affecting subcutaneous or submucosal tissues. HAE attacks recur with unpredictable severity and frequency throughout patients' lives; long-term prophylaxis is essential for some patients. In the absence of head-to-head studies, indirect treatment comparison (ITC) of long-term prophylactic agents is a valid approach to evaluate comparative efficacy. METHODS: We conducted an ITC using data from the placebo-controlled HELP study (assessing patients receiving lanadelumab 300 mg every 2 or 4 weeks) and the 12-week, parallel arm, crossover CHANGE study (assessing intravenous C1-INH). Outcomes of interest were attack rate ratio (ARR) and time to attack after day 0 (TTA0) and after day 70 (TTA70). Two ITC methodologies were used: a Bayesian approach using study results to update non-informative prior distributions to posterior distributions on relative treatment effects, and a frequentist approach using patient-level data from HELP and CHANGE to generate Poisson regressions (for ARR) and Cox models (for TTA0 and TT70). RESULTS: Both Bayesian and frequentist analyses suggested that lanadelumab reduced HAE attack rate by 46-73% versus intravenous C1-INH. Relative to intravenous C1-INH, risk of first attack after day 0 was comparable between intravenous C1-INH and both lanadelumab doses; risk of first attack after day 70 was reduced by 81-83% with lanadelumab 300 mg every 2 weeks, compared with C1-INH. CONCLUSIONS: Findings from these two ITC methodologies support the favorable efficacy of lanadelumab in reducing the HAE attack rate and extending attack-free intervals in patients with HAE.

Clinical characteristics and burden of illness in patients with hereditary angioedema: findings from a multinational patient survey.

BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, genetic disease characterized by unpredictable, recurrent, and potentially fatal swelling of the skin and mucous membranes. We conducted a noninterventional, cross-sectional, web-based survey of patients with a self-reported diagnosis of HAE type 1/2 in Australia, Austria, Canada, France, Germany, Spain, Switzerland, and the United Kingdom to gain a comprehensive real-world understanding of the characteristics of HAE and its burden from the perspective of the patient. The survey included questions on clinical and demographic characteristics, burden of disease, and treatment. Instruments used to measure patient-reported outcomes included the Angioedema Quality of Life questionnaire (AE-QoL), 12-Item Short-Form Health Survey (SF-12v2), Angioedema Control Test (AECT), Hospital Anxiety and Depression Scale (HADS), and Work Productivity and Impairment questionnaire (WPAI). Data were analyzed with descriptive statistics. RESULTS: A total of 242 patients (67.4% female; mean [range] age 43.8 [18-92] years) completed the survey. The mean (SD) age at first symptoms was 11.5 (8.9) years, while diagnosis occurred at 20.8 (13.2) years. Patients reported a mean (SD) of 12.5 (14.1) attacks in the past 6 months. The most recent attack occurred within the past month in 79.7% of patients; most were of moderate severity, 6.6% affected the larynx, 21.9% lasted ≥ 3 days, and 76.4% were treated with on-demand medication. Hospitalizations and emergency/urgent care visits were highest for patients with more attacks. At the time of the survey, 62.4% of patients were using long-term prophylaxis, including 34.4% using androgens. Moderate to severe anxiety and depression were reported in 38.0% and 17.4% of patients, respectively, as measured using the HADS. The severity of anxiety and depression was associated with poorer quality of life and productivity, measured using the AECT (mean overall score 8.00 [moderate perceived disease control]), AE-QoL, WPAI, and SF-12v2. Scores for AECT, AE-QoL, and WPAI were also worse with a higher number of attacks. CONCLUSIONS: This survey study of a broad international sample of patients with HAE showed that despite the availability of on-demand treatment and long-term prophylaxis for the prevention of attacks, patients across a wide geographical area continue to have high disease activity, likely due to restrictions in the availability of medications or incorrect use. Subsequently, significant disease burden, including impaired quality of life and mental health and decreased productivity, was evident. Increased patient education and access to newer, more effective therapies are needed.

Economic evaluations of screening strategies for the early detection of colorectal cancer in the average-risk population: A systematic literature review.

BACKGROUND: Colorectal cancer (CRC) screening has proven effective in reducing CRC mortality. This study aimed to systematically review, and evaluate the reporting quality, of the economic evidence regarding CRC screening in average-risk individuals. METHODS: Databases searched included Medline, EMBASE, National Health Service Economic Evaluation, Database of Abstracts of Reviews of Effects, Cost-Effectiveness Analysis registry, EconLit, and Health Technology Assessment database. Eligible studies were cost-effectiveness and cost-utility analyses comparing CRC screening strategies in average-risk individuals, published in English or Spanish, between January 2012 and November 2018. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Of 1,993 publications initially retrieved, 477 were excluded by duplicate review, 1,449 by title/abstract review, and 34 by full-text review. Finally, 33 publications were included in the qualitative synthesis. Most studies were conducted in Europe (36,4%), followed by United States (24,2%) and Asia (24,2%). The main screening modalities considered were fecal immunochemical tests (70%), colonoscopy (67%), guaiac fecal occult blood test (42%) and flexible sigmoidoscopy (30%). In most studies, CRC screening was deemed cost-effective compared to no screening. Sensitivity analyses indicated that cost of CRC screening tests, adherence to screening, screening test sensitivity, and cost of CRC treatment had the greatest impact on cost-effectiveness results across studies. The majority of studies (73%) adequately reported at least 50% of the items included in the CHEERS checklist. Least well reported items included setting, study perspective, discount rate, model choice, and methods to identify effectiveness data or to estimate resource use and costs. CONCLUSIONS: CRC screening is an efficient alternative to no screening. Nevertheless, it is not possible to conclude which strategy should be preferred for population-based screening programs. Although we observed an overall good adherence to CHEERS recommendations, there is still room for improvement in economic evaluations reporting in this field.

Correction: Economic evaluation of the one-hour rule-out and rule-in algorithm for acute myocardial infarction using the high-sensitivity cardiac troponin T assay in the emergency department.

[This corrects the article DOI: 10.1371/journal.pone.0187662.].

Economic evaluation of the one-hour rule-out and rule-in algorithm for acute myocardial infarction using the high-sensitivity cardiac troponin T assay in the emergency department.

BACKGROUND: The 1-hour (h) algorithm triages patients presenting with suspected acute myocardial infarction (AMI) to the emergency department (ED) towards "rule-out," "rule-in," or "observation," depending on baseline and 1-h levels of high-sensitivity cardiac troponin (hs-cTn). The economic consequences of applying the accelerated 1-h algorithm are unknown. METHODS AND FINDINGS: We performed a post-hoc economic analysis in a large, diagnostic, multicenter study of hs-cTnT using central adjudication of the final diagnosis by two independent cardiologists. Length of stay (LoS), resource utilization (RU), and predicted diagnostic accuracy of the 1-h algorithm compared to standard of care (SoC) in the ED were estimated. The ED LoS, RU, and accuracy of the 1-h algorithm was compared to that achieved by the SoC at ED discharge. Expert opinion was sought to characterize clinical implementation of the 1-h algorithm, which required blood draws at ED presentation and 1h, after which "rule-in" patients were transferred for coronary angiography, "rule-out" patients underwent outpatient stress testing, and "observation" patients received SoC. Unit costs were for the United Kingdom, Switzerland, and Germany. The sensitivity and specificity for the 1-h algorithm were 87% and 96%, respectively, compared to 69% and 98% for SoC. The mean ED LoS for the 1-h algorithm was 4.3h-it was 6.5h for SoC, which is a reduction of 33%. The 1-h algorithm was associated with reductions in RU, driven largely by the shorter LoS in the ED for patients with a diagnosis other than AMI. The estimated total costs per patient were £2,480 for the 1-h algorithm compared to £4,561 for SoC, a reduction of up to 46%. CONCLUSIONS: The analysis shows that the use of 1-h algorithm is associated with reduction in overall AMI diagnostic costs, provided it is carefully implemented in clinical practice. These results need to be prospectively validated in the future.

Long-Term Prediction of the Demand of Colonoscopies Generated by a Population-Based Colorectal Cancer Screening Program.

OBJECTIVE: To estimate the long-term need for colonoscopies after a positive fecal immunochemical test (FIT) and post-polypectomy surveillance in the context of a population-based colorectal cancer (CRC) screening program. METHODS: A discrete-event simulation model was built to reproduce the process of CRC screening and post-polypectomy surveillance following European guidelines in a population of 100,000 men and women aged 50-69 years over a 20-year period. Screening consisted of biennial FIT and colonoscopy in participants with positive results. The model was mainly fed using data from the first and second rounds of a Spanish program (2010-2013). Data on post-polypectomy surveillance results were obtained from the literature. A probabilistic multivariate sensitivity analysis was performed on the effect of participation, FIT positivity, and adherence to surveillance colonoscopies. The main outcome variables were the number of colonoscopies after a positive FIT, surveillance colonoscopies, and the overall number of colonoscopies. RESULTS: An average yearly number of 1,200 colonoscopies after a positive FIT were predicted per 100,000 inhabitants with a slight increase to 1,400 at the end of the 20-year period. Surveillance colonoscopies increased to an average of 1,000 per 100,000 inhabitants in the long-term, showing certain stabilization in the last years of the 20-year simulation horizon. The results were highly sensitive to FIT positivity. CONCLUSIONS: Implementing a population-based CRC screening program will increase the demand for colonoscopies, which is expected to double in 20 years, mainly due to an increase in surveillance colonoscopies.

Direct costs of unintended pregnancy in Spain.

OBJECTIVE: The aim of the study was to estimate the burden and direct medical costs of unintended pregnancy to the public payer in Spain. METHODS: An economic model evaluating the costs and outcomes of contraceptive use over a 1-year period was constructed for women in Spain aged 15 to 44 years at risk of pregnancy. Model inputs were derived from published literature and national survey data. Outcomes evaluated included: (i) the annual number of unintended pregnancy events and their cost; (ii) the proportion of unintended pregnancy events and their cost due to non-adherence; and (iii) the use and cost of contraceptive methods in Spain. RESULTS: Of the total number of pregnancies, 35% are estimated to be unintended and are associated with a direct cost burden of €292.8 million per year. Most unintended pregnancies (26%) occur in women aged 30 to 34 years, whilst 69% of the total cost burden is estimated to be attributable to poor adherence to contraceptive methods. CONCLUSIONS: The cost associated with unintended pregnancy is high. The major proportion of the burden is estimated to be attributable to imperfect adherence and is likely avoidable. Shifts in patterns of contraceptive use, combined with measures to improve adherence, could have a substantial and positive impact on this burden.

Speed cameras in an urban setting: a cost-benefit analysis.

BACKGROUND: To perform a cost-benefit analysis of the installation of speed cameras on the beltways of Barcelona. METHODS: The analysis was performed from the society perspective over a 2-year period using a controlled before-and-after study design. The net benefit was calculated using, as benefits, the willingness to pay for the estimated number of people who avoided injury as a consequence of the intervention, subtracting costs and savings. Sensitivity analyses were performed using the maximum and minimum estimated number of people who avoided injury, assuming that there was a minimum of one death avoided, using the maximum value of a statistical life, assigning all implementation costs to the first year and assuming there was no time lost due to speed reduction. RESULTS: Base case results showed a net benefit of €6.8 million. Sensitivity analyses suggested that net benefits could range from €5.6 to €23.1 million over 2 years. CONCLUSIONS: The use of speed cameras in urban areas has a favourable economic impact even when assessed using conservative assumptions.

[Performance assessment of health services in Catalonia (Spain): evaluation of initial results of the Catalan healthcare service project]. / Análisis del desempeño de los servicios sanitarios de Cataluña: evaluación de los primeros resultados del proyecto demostrativo.

Performance assessment of healthcare services is receiving greater attention due to increasing health care expenditures, greater expectations among the population, and the need to obtain results from the invested resources. Taking advantage of the existing experience of the Agència de Salut Pública de Barcelona and the Consorci Sanitari de Barcelona, which compared the healthcare services of Barcelona and Montreal, a grant from the Agència d'Avaluació de Tecnologia i Recerca Mèdiques, and the health planning interest of the Departament de Salut, the performance assessment of the Catalan healthcare service project was started in Catalonia in 2005. This article aims to present the development of the project, to provide some examples that illustrate the kind of numerical and graphical information that could be obtained and the kind of analysis that could be performed, to provide possible explanations for the results shown, and to discuss some limitations and implications. Currently, the added value of this project is that it identifies the extent to which the healthcare system is achieving its objectives, establishes a set of homogeneous indicators that could be used in the future, and is a key tool in the development of the Central de Resultats del Departament de Salut de la Generalitat de Catalunya.

[Evaluation of the quality of life of patients with localizad prostate cancer: validation of the Spanish version of the EPIC]. / Evaluación de la calidad de vida de los pacientes con cáncer de próstata localizado: validación de la versión española del cuestionario EPIC.

BACKGROUND AND OBJECTIVE: The EPIC (Expanded Prostate Cancer Index Composite) is a specific questionnaire for patients with prostate cancer designed to evaluate the impact of treatments on their quality of life. It contains 50 items divided in 4 summaries: urinary, intestinal, sexual and hormonal. The objective was to adapt the EPIC to Spanish and to evaluate its metric characteristics. METHOD: The method followed for the adaptation included translation and back-translation. The metric characteristics were evaluated in 50 patients from each treatment -prostatectomy, brachytherapy and external radiotherapy-, all of whom were administered the EPIC, SF-36 and FACT (Functional Assessment of Cancer Therapy) pre and post intervention. Reliability was evaluated with the Cronbach alpha coefficient. Construct validity was assessed by means of correlations between subscales of the EPIC and questionnaires, and comparing the patients with and without hormonal therapy (T-test). In order to value sensitivity to change, the standardized effect size was calculated after the intervention. RESULTS: The Cronbach's alpha of the EPIC summaries was high (0.66-0.89). The correlations between the EPIC and the FACT were near or higher than 0.4. Differences were found in the hormonal and sexual summaries between the patients with and without hormonal therapy (p<0.01). The standardized effect size was large (>0.8) in the urinary (3 groups) and sexual (group of prostatectomy) summary, and moderate in the intestinal summary (0.6 and 0.7) for the 2 groups of radiotherapy. CONCLUSIONS: The Spanish version of the EPIC is reliable, valid and presents an excellent sensitivity to change, being a useful tool to compare the impact in the quality of life of the 3 treatments.

Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures.

OBJECTIVE: This study was aimed to develop a tool for the standardized assessment of patient-reported outcomes (PROs) to assist the choice of instruments. METHODS: An expert panel adapted the eight attributes proposed by the Medical Outcomes Trust as evaluation review criteria, created items to evaluate them, and included a response scale for each item. A pilot test was designed to test the new tool's feasibility and to obtain preliminary information concerning its psychometric properties. The Spanish versions of five measures were selected for assessment: the SF-36 Health Survey, the Nottingham Health Profile, the COOP-WONCA charts, the EuroQol-5D, and the Quality of Life Questionnaire EORTC-QLQ-C30. We assessed the new tool's reliability (Cronbach's alpha and intraclass correlation coefficient [ICC]) and construct validity. RESULTS: The new EMPRO (Evaluating the Measurement of Patient-Reported Outcomes) tool has 39 items covering eight key attributes: conceptual and measurement model, reliability, validity, responsiveness, interpretability, burden, alternative modes of administration, and cross-cultural and linguistic adaptations. Internal consistency was high (alpha = 0.95) as was interrater concordance (ICC: 0.87-0.94). Positive associations consistent with a priori hypotheses were observed between EMPRO attribute scores and the number of articles identified for the measures, the years elapsed since the publication of the first article, and the number of citations. CONCLUSION: A new tool for the standardized assessment of PRO measures is available. It has shown good preliminary reliability and validity and should be a useful aid to investigators who need to choose between alternative measures. Further assessment of the tool is necessary.

[Development of a geographic filter for PubMed to identify studies performed in Spain]. / Construcción de un filtro geográfico para la identificación en PubMed de estudios realizados en España.

INTRODUCTION AND OBJECTIVES: The increasing size of the PubMed (Medline) database has made it necessary to develop specific tools for information retrieval (i.e., filters). The current configuration of the Limits option in PubMed does not enable searches to be limited according to geographic criteria. Our objectives, therefore, were a) to develop a geographic filter for the retrieval from PubMed of studies performed in the Spanish population, and b) to assess its performance. METHODS: A second-generation filter was constructed by reviewing previous strategies. It involved the selection of three types of record that included: a) the term Spain in different languages; b) Spanish place names (i.e., mainly those of autonomous regions and provinces), and c) acronyms for health services in autonomous regions. The performance of the filter (i.e., its sensitivity and specificity) was assessed in a representative sample (i.e., clinical trials indexed in PubMed under the MeSH term Myocardial Infarction) by comparison with the results of a manual search (the gold standard). In addition, the filter's performance was also evaluated by comparing it with a simple search for the term Spain[ad]. RESULTS: Use of the filter retrieved 74 (98.7%) of the relevant references. The sensitivity (88.1%) was higher than that of the simple search strategy (45.8%), and excellent specificity (100%) was achieved in both cases. CONCLUSIONS: A geographic filter has been developed for identifying studies in PubMed that involve the Spanish population.