An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

Hereditary Angioedema With Normal C1 Inhibitor: US Survey of Prevalence and Provider Practice Patterns.

BACKGROUND: Hereditary angioedema (HAE) with normal C1-INH (HAE-nl-C1INH) is phenotypically similar to HAE resulting from C1-INH deficiency (HAE-C1INH). Confirmatory diagnostic tests for HAE-nl-C1INH are limited and few clinical study data exist regarding management of the condition. Therefore, survey studies may provide initial estimates of prevalence, diagnosis, and management patterns of this condition. OBJECTIVE: To estimate the prevalence and describe current management patterns for HAE-nl-C1INH in the United States (US). METHODS: We conducted an Internet-based survey of US physicians to estimate the prevalence of the HAE-nl-C1INH population in the United States. Potential participating physicians were identified from the US Hereditary Angioedema Association database and IQVIA Xponent prescription database. Eligible physicians were invited to complete an online survey between June and September 2021. RESULTS: A total of 113 physicians provided data for the estimation of HAE-nl-C1INH prevalence and 81 physicians treating HAE-nl-C1INH patients provided data about treatment patterns. In bias-corrected analysis, we estimated 1,230 to 1,331 HAE-nl-C1INH patients within the United States between May 2019 and April 2020. Mean time to diagnosis for HAE-nl-C1INH was approximately 6 years (range, 2.4-13.5 years). Response to medication was commonly used to inform diagnosis (antihistamine response or nonresponse used by 73% of physician respondents, corticosteroids by 57%, or HAE-specific medications by 74%), and Factor XII genetic testing was used by 43%. CONCLUSIONS: These survey data provide estimates of HAE-nl-C1INH prevalence in the United States as well as current diagnosis and management strategies. Results may be useful for developing studies to assess treatment efficacy and safety, and potentially improve the diagnosis for and management of this patient population.

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE. METHODS: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial. RESULTS: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106  M-1  s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage. CONCLUSION: KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.

KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study results.

BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin. OBJECTIVE: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults. METHODS: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 × 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals. RESULTS: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC0-24) of 18,600 (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours. CONCLUSION: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated. GOV IDENTIFIER: NCT04349800.

Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.

BACKGROUND: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management. METHODS: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria. RESULTS: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark. CONCLUSIONS: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.

The effect of walking on cardiorespiratory fitness in adults with knee osteoarthritis.

Walking programs alone or in combination with behavioral interventions have proven effective at improving quality of life among older adults with osteoarthritis (OA). It is unclear, however, whether the combination of both of these treatments is more effective at improving cardiorespiratory fitness in older adults with knee OA than a walking program alone or than unsupervised self-directed walking. In this study, we assessed cardiorespiratory fitness with 3 programs: a structured supervised community-based aerobic walking program with a behavioral intervention (WB; n = 41); a supervised program of walking only (W; n = 42); and an unsupervised self-directed walking program (n = 32). We measured maximal oxygen uptake (V̇O2peak), exercise test duration, and workload, heart rate, and ventilation at maximum aerobic capacity in older adults with knee OA after 6 months of WB, W, or self-directed walking. Overall, V̇O2peak improved by 4% in female walkers (+0.9 ± 2.5 mL O2·kg(-1)·min(-1); p < 0.001) and 5% in male walkers (+1.3 ± 2.7 mL O2·kg(-1)·min(-1); p < 0.001), and the change in fitness was similar with all 3 walking interventions. In conclusion, low- to moderate-intensity walking may improve and (or) prevent decrements in cardiorespiratory fitness in older adults with OA. This response was comparable in supervised walkers with and without a behavioral intervention and in unsupervised self-directed walkers.

Abatacept or infliximab for patients with rheumatoid arthritis and inadequate response to methotrexate: an Italian trial-based and real-life cost-consequence analysis.

OBJECTIVES: In the 1-year, double-blind, placebo-controlled ATTEST trial, efficacy of abatacept or infliximab versus placebo was reported in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). The current study estimated trial-based and real-life costs of abatacept and infliximab for achieving pre-defined remission or low disease activity state (LDAS). METHODS: Quantity of drug, serious adverse event (SAE) rates and time (months) in remission or LDAS were taken from ATTEST for the trial-based calculation to derive a cost per remitting/LDAS patient and a cost per patient-month in remission/LDAS. Trial-based and real-life scenarios were performed. RESULTS: The annual trial-based costs per remitting/LDAS patient were €70.238/€37.208 for abatacept and €85.565/€46.602 for infliximab. In the first 6 months of the ATTEST trial, costs per patient-month in remission/LDAS were higher for abatacept (€11.024 and €6.018, respectively), relative to infliximab (€8.347 and €4.174, respectively). Over the full 12-month trial period cost per month in remission/LDAS estimates were only slightly in favour of infliximab (€6.959/€3.625) relative to abatacept (€7.297/€3.909). Assuming extension of treatment under real life conditions the cost per month in remission/LDAS turned substantially in favour of abatacept (€5.321/€2.819), as compared to infliximab (€7.189/€3.916). The higher initiation cost for abatacept to achieve remission/LDAS would be offset after a total 14.6 and 16.1 months of treatment, respectively, if treatment extended beyond 6 months under real-life conditions. These results proved to be robust when it was assumed that the (i) sharing of vials across patients completely averted infliximab wastage, (ii) AE risks were similar and (iii) onset of response was slower for abatacept. CONCLUSIONS: Our findings suggest a lower cost-consequence for abatacept during real-life treatment.

The implementation of a community-based aerobic walking program for mild to moderate knee osteoarthritis: a knowledge translation randomized controlled trial: part II: clinical outcomes.

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the world, as it is appears to be prevalent among 80% of individuals over the age of 75. Although physical activities such as walking have been scientifically proven to improve physical function and arthritic symptoms, individuals with OA tend to adopt a sedentary lifestyle. There is therefore a need to improve knowledge translation in order to influence individuals to adopt effective self-management interventions, such as an adapted walking program. METHODS: A single-blind, randomized control trial was conducted. Subjects (n = 222) were randomized to one of three knowledge translation groups: 1) Walking and Behavioural intervention (WB) (18 males, 57 females) which included the supervised community-based aerobic walking program combined with a behavioural intervention and an educational pamphlet on the benefits of walking; 2) Walking intervention (W) (24 males, 57 females) wherein participants only received the supervised community-based aerobic walking program intervention and the educational pamphlet; 3) Self-directed control (C) (32 males, 52 females) wherein participants only received the educational pamphlet. One-way analyses of variance were used to test for differences in quality of life, adherence, confidence, and clinical outcomes among the study groups at each 3 month assessment during the 12-month intervention period and 6-month follow-up period. RESULTS: The clinical and quality of life outcomes improved among participants in each of the three comparative groups. However, there were few statistically significant differences observed for quality of life and clinical outcomes at long-term measurements at 12-months end of intervention and at 6- months post intervention (18-month follow-up). Outcome results varied among the three groups. CONCLUSION: The three groups were equivalent when determining the effectiveness of knowledge uptake and improvements in quality of life and other clinical outcomes. OA can be managed through the implementation of a proven effective walking program in existing community-based walking clubs. TRIAL REGISTRATION: Current Controlled Trials IRSCTNO9193542.

The implementation of a community-based aerobic walking program for mild to moderate knee osteoarthritis (OA): a knowledge translation (KT) randomized controlled trial (RCT): Part I: The Uptake of the Ottawa Panel clinical practice guidelines (CPGs).

BACKGROUND: The implementation of evidence based clinical practice guidelines on self-management interventions to patients with chronic diseases is a complex process. A multifaceted strategy may offer an effective knowledge translation (KT) intervention to promote knowledge uptake and improve adherence in an effective walking program based on the Ottawa Panel Evidence Based Clinical Practice Guidelines among individuals with moderate osteoarthritis (OA). METHODS: A single-blind, randomized control trial was conducted. Patients with mild to moderate (OA) of the knee (n=222) were randomized to one of three KT groups: 1) Walking and Behavioural intervention (WB) (18 males, 57 females) which included the supervised community-based aerobic walking program combined with a behavioural intervention and an educational pamphlet on the benefits of walking for OA; 2) Walking intervention (W) (24 males, 57 females) wherein participants only received the supervised community-based aerobic walking program intervention and the educational pamphlet; 3) Self-directed control (C) (32 males, 52 females) wherein participants only received the educational pamphlet. One-way analyses of variance were used to test for differences in quality of life, adherence, confidence, and clinical outcomes among the study groups at each 3 month assessment during the 12-month intervention period and 6-month follow-up period. RESULTS: Short-term program adherence was greater in WB compared to C (p<0.012) after 3 months. No statistical significance (p> 0.05) was observed for long-term adherence (6 to 12 months), and total adherence between the three groups. The three knowledge translation strategies demonstrated equivalent long-term results for the implementation of a walking program for older individuals with moderate OA. Lower dropout rates as well as higher retention rates were observed for WB at 12 and 18 months. CONCLUSION: The additional knowledge translation behavioural component facilitated the implementation of clinical practice guidelines on walking over a short-term period. More studies are needed to improve the long-term walking adherence or longer guidelines uptake on walking among participants with OA. Particular attention should be taken into account related to patient's characteristic and preference. OA can be managed through the implementation of a walking program based on clinical practice guidelines in existing community-based walking clubs as well as at home with the minimal support of an exercise therapist or a trained volunteer. TRIAL REGISTRATION: Current Controlled Trials IRSCTNO9193542.

Ottawa panel evidence-based clinical practice guidelines for aerobic walking programs in the management of osteoarthritis.

OBJECTIVE: To update the Evidence-Based Clinical Practice Guidelines (EBCPGs) on aerobic walking programs for the management of osteoarthritis (OA) of the knee. DATA SOURCES: A literature search was conducted using the electronic databases MEDLINE, PubMed, and the Cochrane Library for all studies related to aerobic walking programs for OA from 1966 until February 2011. STUDY SELECTION: The literature search found 719 potential records, and 10 full-text articles were included according to the selection criteria. The Ottawa Methods Group established the inclusion and exclusion criteria regarding the characteristics of the population, by selecting adults of 40 years old and older who were diagnosed with OA of the knee. DATA EXTRACTION: Two reviewers independently extracted important information from each selected study using standardized data extraction forms, such as the interventions, comparisons, outcomes, time period of the effect measured, and study design. The statistical analysis was reported using the Cochrane collaboration methods. An improvement of 15% or more relative to a control group contributes to the achievement of a statistically significant and clinically relevant progress. A specific grading system for recommendations, created by the Ottawa Panel, used a level system (level I for randomized controlled studies and level II for nonrandomized articles). The strength of the evidence of the recommendations was graded using a system with letters: A, B, C+, C, D, D+, or D-. DATA SYNTHESIS: Evidence from 7 high-quality studies demonstrated that facility, hospital, and home-based aerobic walking programs with other therapies are effective interventions in the shorter term for the management of patients with OA to improve stiffness, strength, mobility, and endurance. CONCLUSIONS: The greatest improvements were found in pain, quality of life, and functional status (grades A, B, or C+). A common limitation inherent to the EBCPGs is the heterogeneity of studies included with regards to the characteristics of the population, the interventions, the comparators, the outcomes, the period of time, and the study design. It is strongly recommended to use the Cochrane Risk of Bias Summary assessment to evaluate the methodologic quality of the studies and to consider avenues for future research on how aerobic walking programs would be beneficial in the management of OA of the hip.

Is a mass immunization program for pandemic (H1N1) 2009 good value for money? Evidence from the Canadian Experience.

In response to the pandemic H1N1 influenza 2009 outbreak, many jurisdictions undertook mass immunization programs that were among the largest in recent history. The objective of this study was to determine the cost-effectiveness of the mass H1N1 immunization program in Ontario, Canada's most populous province (population 13,000,000). This analysis suggests that a mass immunization program as carried out in Ontario and many other high-income health care systems in response to H1N1 2009 was effective in preventing influenza cases and health care resource use and was also highly cost-effective despite the substantial program cost.

Economic appraisal of Ontario's Universal Influenza Immunization Program: a cost-utility analysis.

BACKGROUND: In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP). METHODS AND FINDINGS: A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted. CONCLUSIONS: Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.

The OMERACT Initiative. Towards a reference approach to derive QALY for economic evaluations in rheumatology.

Within the OMERACT Economics Workgroup, an initiative was started to work towards consensus on the approach to calculate quality-adjusted life-years (QALY) in rheumatology. We report on a first meeting May 7, 2008, in Toronto attended by rheumatologists and experts in QALY. Following a summary of an international QALY workshop of pharmacoeconomists conducted under the umbrella of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), participating experts identified a series of high-level generic principles to be considered for QALY estimations. The OMERACT workgroup then addressed specific issues rheumatologists should concentrate on in research to build consensus on QALY in rheumatology; discussion was based on results of a Web-based survey, conducted prior to the meeting, to identify attributes of a QALY considered important and approaches considered suitable for the QALY estimations in rheumatology. One priority was to further explore indirect approaches to QALY estimation as representation of patients' preference for health in clinical decisions and to explore the additional value of patients' preferences versus societal preferences in allocation decisions. The role of the different descriptive systems and their influence on the QALY, the role of the visual analog scale to value preferences, and comparison of methods to integrate utility over time were also identified as research priorities. Approaches should be easy to apply, easy to understand by different parties, reproducible, and sensitive to change.

A coordinator program in post-fracture osteoporosis management improves outcomes and saves costs.

BACKGROUND: The orthopaedic unit at a university teaching hospital hired an osteoporosis coordinator to identify patients with a fragility fracture and to coordinate their education, assessment, referral, and treatment of underlying osteoporosis. We report the results of an analysis of the cost-effectiveness of the use of a coordinator (in comparison with the use of no coordinator) in avoiding future costs of subsequent hip fracture. METHODS: A one-year decision-analysis model was developed. The health outcome was subsequent hip fracture; only direct hospital costs were considered. With use of patient-level data from a previously described coordinator program and data from the literature, the expected annual incidence of subsequent hip fracture was calculated, on the basis of the type of index fracture (wrist, hip, humerus, other), attribution to osteoporosis, age, and gender. The rate of patient referral, the initiation of osteoporosis treatment, and adherence to therapy were modeled to modify the expected incidence of future hip fracture in the presence of a coordinator (with use of data from the program) and in the absence of a coordinator (with use of data from the literature). Sensitivity analysis modeling techniques were used to assess variable uncertainty and to evaluate coordinator cost-effectiveness. RESULTS: Deterministic cost-effectiveness analysis showed that a tertiary care center that hired an osteoporosis coordinator who manages 500 patients with fragility fractures annually could reduce the number of subsequent hip fractures from thirty-four to thirty-one in the first year, with a net hospital cost savings of C$48,950 (Canadian dollars in year-2004 values), with use of conservative assumptions. Probabilistic sensitivity analysis indicated a 90% probability that hiring a coordinator costs less than C$25,000 per hip fracture avoided. Hiring a coordinator is a cost-saving measure even when the coordinator manages as few as 350 patients annually. Greater savings are anticipated after the first year and when additional costs such as rehabilitation and dependency costs are considered. CONCLUSIONS: Employment of an osteoporosis coordinator to manage outpatients and inpatients who have fragility fractures is predicted to reduce the incidence of future hip fractures and to save money (a dominant strategy). A probabilistic sensitivity analysis showed a high probability of cost-effectiveness of this intervention from the hospital cost perspective.

Rapid and sustained improvement in health-related quality of life and utility for 72 weeks in patients with ankylosing spondylitis receiving etanercept.

OBJECTIVE: To examine the longterm effect of etanercept (ETN) therapy on health-related quality of life (HRQOL) and utility in patients with ankylosing spondylitis. METHODS: Patients completing a 24-week placebo-controlled trial were continued on ETN in a 72-week open-label extension study. Short Form-36 (SF-36), EuroQOL-5D (EQ-5D), and EuroQOL visual analog scale (EQ-VAS) scores were collected at open-label baseline and every 12 weeks thereafter. Mental and physical component scores (MCS and PCS) of the SF-36, EQ-5D and SF-6D utility scores, and quality-adjusted life-years (QALY) were calculated. RESULTS: 257 patients [129 previous placebo (PLA) and 128 ETN recipients] enrolled in this open-label extension study, and 85% completed the 72-week followup. PCS, EQ-5D and SF-6D utilities, and EQ-VAS were significantly lower at open-label baseline in the previous PLA group (PLA/ETN group) than in the previous ETN group (ETN/ETN group; all p < 0.001). At week 12, PCS and MCS, EQ-5D and SF-6D utility scores, and EQ-VAS were similar in the PLA/ETN and ETN/ETN groups. As expected, mean change in EQ-5D in the PLA/ETN group was significantly greater than that for SF-6D (0.18 vs 0.06; p < 0.0001). HRQOL and utility improvements were maintained in both groups for up to 72 weeks. The average 72-week QALY gain per person in the PLA/ETN group was 0.24 and 0.10 for EQ-5D and SF-6D, respectively. CONCLUSION: Patients continuing ETN therapy sustained HRQOL and utility improvements attained during the original PLA-controlled trial. Patients previously taking PLA showed rapid and sustained improvements in HRQOL and utility and substantial QALY gain with ETN therapy.

Considerations and preliminary proposals for defining a reference case for economic evaluations in ankylosing spondylitis.

Since healthcare resources are scarce, choices have to be made on how they will be allocated. The use of economic evaluations using cost-effectiveness analyses has increased rapidly as policymakers have realized their value in maximizing the population's benefits (in terms of length of life and health status) within a given budget. Following efforts by OMERACT to create reference case definitions for the conduct of economic evaluation in rheumatoid arthritis, osteoporosis, and osteoarthritis, we review various methodological areas and research decisions that could benefit from a consensus between researchers, clinicians, and drug developers in terms of an ankylosing spondylitis (AS) reference case. Ten methodological issues are presented that will be important for future development of evaluations. Tentative proposals to define the issues in a reference case for AS are made, along with recommendations for further research.

Cost effectiveness analysis of disease modifying antirheumatic drugs in rheumatoid arthritis.

The objective was to assess the cost-effectiveness of various DMARDs compared with antimalarials (AM) for rheumatoid arthritis (RA) treatment. The data on disease activity, functional status and societal costs were collected from a 1-year cohort of 152 patients with RA receiving at least one DMARD for > or = 6 months. Incremental cost effectiveness ratio (ICER) was calculated from the societal costs of DMARD treatment compared with AM per one unit of HAQ improvement. All costs were presented in 2001 US dollars. Mean (SD) societal cost of AM treatment was US$ 2,285 (1,154) per patient per year. MTX + AM was less costly and more effective than AM, as the ICER of this combination would save US$ 834 per 1 U of HAQ improvement. MTX + SSZ, leflunomide, and triple therapy (AM + MTX + SSZ) were more effective than AM with additional costs. RA treatment with non MTX-based DMARDs was not cost-effective.

The economic burden of rheumatoid arthritis in a developing nation: results from a one-year prospective cohort study in Thailand.

OBJECTIVE: To assess annual direct and indirect costs in a prospective cohort of patients with rheumatoid arthritis (RA) in Thailand from the societal perspective. METHODS: Data on costs and intangible losses were prospectively collected at regular intervals over a one-year period from 158 RA patients who attended a major tertiary care facility in Bangkok, Thailand. Direct medical, direct nonmedical, indirect, and total costs were estimated according to patients' respective health insurance conditions and converted to 2001 US dollars using published purchasing power parity estimates. Sensitivity analyses were performed and the predictors of costs and intangible losses were investigated. RESULTS: The average societal cost of RA was estimated to be 2682 US dollars, 41.4% of patients' average annual income. Average direct and indirect costs were estimated to amount to 2135 US dollars and 547 US dollars per patient per year, respectively. Seventy-three patients (46.2%) experienced at least one event of intangible losses and 46 patients (29.1%) had decreased earnings ability because of RA. Poor physical function, joint deformity, high number of disease modifying antirheumatic drugs, and steroid use contributed to higher costs and presence of intangible losses. CONCLUSION: RA consumes a significant proportion of patients' annual average incomes and poses a significant economic burden to society. Since RA mainly affects a working-age population, early and timely treatment of this disease can improve both the suffering and the economic productivity of patients in Thailand.

Primary therapist model for patients referred for rheumatoid arthritis rehabilitation: a cost-effectiveness analysis.

OBJECTIVE: To estimate the incremental cost-effectiveness (ICE) of services from a primary therapist compared with traditional physical therapists and/or occupational therapists for managing rheumatoid arthritis (RA), from the societal perspective. METHODS: Patients with RA were randomly assigned to the primary therapist model (PTM) or traditional treatment model (TTM) for approximately 6 weeks of rehabilitation treatment. Health outcomes were expressed in terms of quality-adjusted life years (QALYs), measured with the EuroQol instrument at baseline, 6 weeks, and 6 months. Direct and indirect costs, including visits to health professionals, use of investigative tests, hospital visits, use of medications, purchases of adaptive aids, and productivity losses incurred by patients and their caregivers, were collected monthly. RESULTS: Of 144 consenting patients, 111 remained in the study after the baseline assessment: 63 PTM (87.3% women, mean age 54.2 years, disease duration 10.6 years) and 48 TTM (79.2% women, mean age 56.8 years, disease duration 13.2 years). From a societal perspective, PTM generated higher QALYs (mean +/- SD 0.068 +/- 0.22) and resulted in a higher mean cost ($6,848 Canadian, interquartile range [IQR] $1,984-$9,320) compared with TTM (mean +/- SD QALY -0.017 +/- 0.24; mean costs $6,266, IQR $1,938-$10,194) in 6 months, although differences were not statistically significant. The estimated ICE ratio was $13,700 per QALY gained (95% nonparametric confidence interval -$73,500, $230,000). CONCLUSION: The PTM has potential to be an alternative to traditional physical/occupational therapy, although it is premature to recommend widespread use of this model in other regions. Further research should focus on strategies to reduce costs of the model and assess the long-term economic consequences in managing RA and other rheumatologic conditions.