Health economic models in hemophilia A and utility assumptions from a clinician's perspective.

BACKGROUND: The clinical benefits of prophylaxis in patients with hemophilia are well-established and include the following: reduced bleeding episodes, prevention of joint damage, decreased inhibitor development, and improved health-related quality of life. However, the cost-effectiveness of prophylaxis is still not clear. PROCEDURES: We reviewed the published hemophilia prophylaxis economic models focusing on utility assumptions. RESULTS: We found six cost-utility studies that compared prophylaxis and on-demand regimens. These studies reported remarkably different results, using utility values based on different assumptions and data sources. CONCLUSIONS: We suggest that cooperation among key stakeholders (clinicians, patient organizations and health-care decision makers) as a means of collecting evidence-based and experiential data to represent both the utility and the quality of life changes for patients with Hemophilia A who are treated with prophylaxis or receive on-demand treatments may represent a winning strategy with which to resolve the outstanding issues related to health technology assessments in the care of patients with hemophilia.

An overview of current trends and gaps in patient-reported outcome measures used in haemophilia.

AIM: This review summarises the importance, recent progress and issues in measuring patient-reported outcomes (PROs) in haemophilia research. METHODS: A critical review of recent advances and trends in measuring haemophilia-related PROs was conducted, using current regulatory guidelines and methodological recommendations to evaluate these instruments. RESULTS: Although regulators, payers and policymakers increasingly consider the patient's perspective to be important in treatment decision-making, to date, few haemophilia intervention studies have meaningfully applied PRO endpoints. Condition-specific PRO instruments have been developed, but most are not fully validated; sensitivity to subgroup differences and changes over time is unclear. Generic PROs and instruments developed for other conditions have been used to measure health-related quality of life (HRQL) in haemophilia patients, but little evidence of their validity for this purpose exists. Haemophilia presents a number of challenges to developing valid, reliable and responsive PRO instruments, including the rarity of the disorder; necessitating research in multiple counties to attain sufficient sample size; the chronic nature of the condition; acute exacerbations of illness; age and geographical region variations with respect to treatment; differences in treatment regimens, range of disease severity and phenotypes; and changes in patients' perceived health status over time. Given that haemophilia begins at birth, the illness has an impact on the lives of caregivers, although the extent of the impact is largely unknown. CONCLUSIONS: Patient perspectives are crucial to understanding the best and most cost-effective haemophilia treatment approaches. More research is needed on the ability of current disease-specific and generic PRO instruments to capture responsiveness to treatments over time and subgroup differences in outcomes. Inclusion of PROs in clinical trials is necessary to answer these questions.

Illustrating the impact of mild/moderate and severe haemophilia on health-related quality of life: hypothesised conceptual models.

INTRODUCTION/AIMS: Haemophilia and its treatment have a significant impact on patients' lives. The study objectives were to understand the impacts of haemophilia and its treatment from the patient perspective and to inform the development of comprehensive health-related quality-of-life (HRQL) conceptual models to illustrate these impacts. METHODS: The study included two phases. Phase I involved a review of literature published from 1995 to 2010, qualitative analysis of six patient (N = 31) and three healthcare provider (N = 15) focus group transcripts, and interviews with two experts to inform draft conceptual models of mild/moderate and severe haemophilia. Phase II involved interviews with 20 haemophilia patients and qualitative analysis of transcripts to confirm the concepts and structure of the conceptual models. RESULTS: The literature search resulted in 66 publications assessing HRQL, four of which were qualitative studies on the impact of haemophilia from the patient perspective. Results from Phase I indicated that acute bleeding events result in pain, swelling, bruising and restricted joint movement; repeated joint bleeds result in chronic symptoms, such as pain and arthropathy. Acute bleeds cause interruptions in daily activities and interfere with work/school. Patients have fears about having bleeds, which can affect their participation in activities, such as sports or crowded events. Patients also expressed feelings of depression, frustration, isolation and embarrassment. Results of Phase II corroborated findings from Phase I. CONCLUSIONS: The conceptual models illustrate the substantial impact of haemophilia and its treatments on patients' lives and can help inform clinical study design and the selection of endpoints to assess treatment benefit.

Patient-reported experience of bleeding events in haemophilia.

BACKGROUND: Patients with haemophilia experience bleeds because of absent or reduced clotting factor. The study objective was to understand the bleeding experience from the patients' perspective. MATERIALS AND METHODS: Individuals with moderate/severe haemophilia participated in interviews and were asked to describe their most recent bleeding experience, including symptoms, signs of onset, impacts, when bleeding stopped and treatment effectiveness. Interview transcripts were analysed using a thematic analysis involving the coding of transcripts to identify key concepts and themes. RESULTS: Twenty males [10 adults, mean age = 41 (19-52); 10 adolescents, mean age = 13 (12-17)] with moderate (n = 5) or severe (n = 15) haemophilia participated. Symptoms signalling bleed onset included pain, swelling, stiffness, tingling/numbness and/or warmth. Participants reported feeling anger and frustration due to the unpredictable nature, pain and inconvenience of the episode. Adults sometimes reported delaying treatment due to inconvenience or cost; adolescents generally treated right away. Reported bleed severity was influenced by pain level, speed of symptom progression, location, continued use of the affected area, recurrence in same location of recent bleed and treatment delay. Participants reported that it was 'easy' to know when the bleed had stopped. Participants reported that symptoms might linger for days before they returned back to 'normal'. CONCLUSIONS: This qualitative study details the substantial impact of an acute bleed from the patient perspective. Given that treatment was reported to be delayed in part due to inconvenience, more convenient treatment options could help reduce delays in treating bleeds and thereby minimise bleed-related impacts. Clinical studies in haemophilia should include validated patient-reported measurements of acute symptoms and bleed severity to comprehensively assess the bleeding event.

Medicaid spending on contraceptive coverage and pregnancy-related care.

OBJECTIVE: Up to 50% of pregnancies are unintended in the United States, and the healthcare costs associated with pregnancy are the most expensive among hospitalized conditions. The current study aims to assess Medicaid spending on various methods of contraception and on pregnancy care including unintended pregnancies. METHODS: We analyzed Medicaid health claims data from 2004 to 2010. Women 14-49 years of age initiating contraceptive methods and pregnant women were included as separate cohorts. Medicaid spending was summarized using mean all-cause and contraceptive healthcare payments per patient per month (PPPM) over a follow-up period of up to 12 months. Medicaid payments were also estimated in 2008 per female member of childbearing age per month (PFCPM) and per member per month (PMPM). Medicaid payments on unintended pregnancies were also evaluated PFCPM and PMPM in 2008. RESULTS: For short-acting reversible contraception (SARC) users, all-cause payments and contraceptive payments PPPM were respectively $365 and $18.3 for oral contraceptive (OC) users, $308 and $19.9 for transdermal users, $215 and $21.6 for vaginal ring users, and $410 and $8.8 for injectable users. For long-acting reversible contraception (LARC) users (follow-up of 9-10 months), corresponding payments were $194 and $36.8 for IUD users, and $237 and $29.9 for implant users. Pregnancy cohort all-cause mean healthcare payments PPPM were $610. Payments PFCPM and PMPM for contraceptives were $1.44 and $0.54, while corresponding costs of pregnancies were estimated at $39.91 and $14.81, respectively. Payments PFCPM and PMPM for contraceptives represented a small fraction at 6.56% ($1.44/$21.95) and 6.63% ($0.54/$8.15), respectively of the estimated payments for unintended pregnancy. CONCLUSIONS: This study of a large sample of Medicaid beneficiaries demonstrated that, over a follow-up period of 12 months, Medicaid payments for pregnancy were considerably higher than payments for either SARC or LARC users. Healthcare payments for contraceptives represented a small proportion of payments for unintended pregnancy when considering the overall Medicaid population perspective in 2008.

Fatigue heralding multiple sclerosis.

BACKGROUND: Fatigue is a common symptom in multiple sclerosis (MS) and is an important determinant of overall well-being and disability. OBJECTIVE: To assess the frequency with which fatigue precedes the diagnosis of MS using a retrospective database analysis. METHODS: Between January 1, 2003 and September 30, 2008, patients diagnosed with fatigue with and without fatigue-related medications within a 3-year period prior to newly diagnosed MS were identified from the MarketScan Databases. All statistical analysis was performed using SAS. RESULTS: Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS. One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed medication for fatigue. CONCLUSION: This study demonstrates that fatigue may herald MS, often by years. A careful history for transient neurological symptoms and a physical examination is warranted in any patient presenting with fatigue.

The cost-effectiveness of the levonorgestrel-releasing intrauterine system for the treatment of idiopathic heavy menstrual bleeding in the United States.

OBJECTIVES: Heavy menstrual bleeding negatively impacts the health and quality of life of about 18 million women in the United States. Although some studies have established the clinical effectiveness of heavy menstrual bleeding treatments, few have evaluated their cost-effectiveness. Our objective was to evaluate the cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) compared with other therapies for idiopathic heavy menstrual bleeding. METHODS: We developed a model comparing the clinical and economic outcomes (from a US payer perspective) of three broad initial treatment strategies over 5 years: LNG-IUS, oral agents, or surgery. Up to three nonsurgical treatment lines, followed by up to two surgical lines, were allowed; unintended pregnancy was possible, and women could discontinue any time during nonsurgical treatments. Menstrual blood loss of 80 ml or more per cycle determined treatment failure. RESULTS: Initiating treatment with LNG-IUS resulted in the fewest hysterectomies (6 per 1000 women), the most quality-adjusted life-years (3.78), and the lowest costs ($1137) among all the nonsurgical strategies. Initiating treatment with LNG-IUS was also less costly than surgery, resulted in fewer hysterectomies (vs. 9 per 1000 for ablation) but was associated with fewer quality-adjusted life-years gained per patient (vs. 3.80 and 3.88 for ablation and hysterectomy, respectively). Sensitivity analyses confirmed these results. CONCLUSIONS: LNG-IUS resulted in the lowest treatment costs and the fewest number of hysterectomies performed over 5 years compared with all other initial strategies and resulted in the most quality-adjusted life-years gained among nonsurgical options. Initial treatment with LNG-IUS is the least costly and most effective option for women desiring to preserve their fertility.

Cardiovascular comorbidities in a United States patient population with hemophilia A: A comprehensive chart review.

PURPOSE: Previous retrospective claims database analyses reported increased prevalence and earlier onset of cardiovascular comorbidities in patients with versus without hemophilia A. A comprehensive chart review was designed to further investigate previous findings. METHODS: This retrospective chart review study was conducted at Henry Ford Health System (Detroit, MI, USA). Baseline demographics, bleeding events, treatment parameters, coexisting diseases, hemophilia-associated events, Charlson Comorbidity Index score, and prevalence of 12 cardiovascular risk factors and associated diseases were compared between hemophilia A and control cohorts. P values from a chi-square test for categorical variables and a t test for continuous variables were calculated. Because of small sample sizes (N = 0-90, most <50), statistical differences between cohorts were also assessed using absolute standardized difference. RESULTS: Both groups were well matched by age, race, healthcare payer, and study year. The Charlson Comorbidity Index score was similar between groups. Prevalence of bleeds, hepatitis B and C, and HIV/AIDS was higher in the hemophilia cohort. Hemophilia A severity was severe, moderate, mild, or unknown in 52.7%, 10.8%, 10.8%, and 25.7% of patients, respectively. Prevalence of 12 cardiovascular risk factors and diseases was numerically higher in the control cohort, but differences were statistically significant (P ≤ 0.05) only for diabetes and hyperlipidemia. Meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation. CONCLUSIONS: This retrospective chart review did not confirm statistically significant differences in cardiovascular comorbidities and their earlier onset in hemophilia A versus controls. Results suggest numerically higher comorbidities in controls.

Analysis of Diagnoses Associated with Multiple Sclerosis-Related In-Hospital Mortality Using the Premier Hospital Database.

BACKGROUND: We sought to compare mortality rates and related diagnoses in hospitalized patients with multiple sclerosis (MS), those with diabetes mellitus (DM), and the general hospitalized population (GHP). METHODS: Patients who died between 2007 and 2011 were identified in the US hospital-based Premier Healthcare Database. Demographic information was collected, mortality rates calculated, and principal diagnoses categorized. RESULTS: Of 55,152 unique patients with MS identified, 1518 died. Mean age at death was 10 years younger for the MS group (63.4 years) than for the DM (73.3 years) and GHP (73.1 years) groups. Age-adjusted mortality rates, based on the 2000 US Standard Million Population, were 1077, 1248, and 1133 per 100,000, respectively. Infection was the most common principal diagnosis at the hospital stay during which the patient died in the MS cohort (43.1% vs. 26.3% and 24.0% in the DM and GHP groups, respectively). Other common principal diagnoses in the MS group included pulmonary (17.5%) and cardiovascular (12.1%) disease. Septicemia/sepsis/septic shock was a secondary diagnosis for 50.7% of patients with MS versus 36.0% and 31.0% of patients in the DM and GHP cohorts, respectively. CONCLUSIONS: Patients with MS had a shorter life span than patients with DM or the GHP and were more likely to have a principal diagnosis of infection at their final hospital stay. However, the database was limited to codes recorded in the hospital; diagnoses received outside the hospital were not captured.

Matching-adjusted indirect comparisons of efficacy of BAY 81-8973 vs two recombinant factor VIII for the prophylactic treatment of severe hemophilia A.

BACKGROUND: No head-to-head trials comparing recombinant factor VIII (rFVIII) products currently exist. This was a matching-adjusted indirect comparison (MAIC) study of efficacy of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) and turoctocog alfa for the prophylaxis of severe hemophilia A. METHODS: A systematic literature review was conducted to identify trials of rAHF-PFM and turoctocog alfa. Comparisons were conducted using BAY 81-8973 individual patient data (IPD) from LEOPOLD trials and published data from rAHF-PFM and turoctocog alfa trials. Differences in outcome reporting were reconciled using transformation of BAY 81-8973 IPD. Patients in pooled LEOPOLD trials were weighted to match baseline characteristics for rAHF-PFM or turoctocog alfa trials using MAICs. After matching, annualized bleed rates (ABRs) were compared using weighted t-tests. RESULTS: Two rAHF-PFM trials and one turoctocog alfa trial were identified. In these trials, rFVIIIs were dosed thrice weekly or every other day; in LEOPOLD trials, BAY 81-8973 was dosed twice- or thrice weekly. Three MAICs were conducted because the two rAHF-PFM trials calculated ABRs differently, matching for age, race, and weight (turoctocog alfa only). BAY 81-8973 had similar ABR of all bleeds vs rAHF-PFM (two trials: 4.8 vs 6.3, 1.9 vs 1.8 [square root transform]) and lower ABR of spontaneous bleeds and trauma bleeds (2.6 vs 4.1, 2.1 vs 4.7; both P<0.05). BAY 81-8973 showed lower ABR of all bleeds and spontaneous bleeds vs turoctocog alfa (4.3 vs 6.5, 2.8 vs 4.3; both P<0.05) and similar ABR of trauma bleeds (1.5 vs 1.6). In subgroup analysis, twice-weekly BAY 81-8973 had similar ABRs of all bleeds, spontaneous bleeds, and trauma bleeds compared to rAHF-PFM and turoctocog alfa. CONCLUSION: This indirect comparison found that prophylaxis with BAY 81-8973, even including the lower frequency of two times a week and lower factor VIII consumption, has efficacy comparable to rAHF-PFM and turoctocog alfa, which were dosed thrice weekly or every other day. The use of IPD enabled adjustments for differences in calculation of ABRs and population characteristics between trials.

Cost-effectiveness analysis of levonorgestrel-releasing intrauterine system (LNG-IUS) 13.5 mg in contraception.

BACKGROUND: Levonorgestrel-releasing intrauterine system (LNG-IUS) 13.5 mg (total content) is a low-dose levonorgestrel intrauterine system for up to 3 years of use. This analysis evaluated the cost-effectiveness of LNG-IUS 13.5 mg in comparison with short-acting reversible contraceptive (SARC) methods in a cohort of young women in the United States from a third-party payer's perspective. STUDY DESIGN: A state transition model consisting of three mutually exclusive health states -- initial method, unintended pregnancy (UP) and subsequent method -- was developed. Cost-effectiveness of LNG-IUS 13.5 mg was assessed vs. SARC methods in a cohort of 1000 women aged 20-29 years. SARC methods comprise oral contraceptives (OC), ring, patch and injections, which are the methods commonly used by this cohort. Failure and discontinuation probabilities were based on published literature, contraceptive uptake was determined by the most recent data from the National Survey of Family Growth, and costs were taken from standard US databases. One-way sensitivity analysis was conducted around key inputs, while scenario analysis assessed a comparison between LNG-IUS 13.5 mg and the existing IUS, LNG-IUS 20 mcg/24 h. The key model output was cost per UP avoided. RESULTS: Compared to SARC methods, initiating contraception with LNG-IUS 13.5 mg resulted in fewer UP (64 UP vs. 276 UP) and lower total costs ($1,283,479 USD vs. $1,862,633 USD, a 31% saving) over the 3-year time horizon. Results were most sensitive to the probability of failure on OC, the probability of LNG-IUS 13.5 mg discontinuation and the cost of live births. Scenario analysis suggests that further cost savings may be generated with the initiation of LNG-IUS 20 mcg/24 h in place of SARC methods. CONCLUSIONS: From a third-party payer perspective, LNG-IUS 13.5 mg is a more cost-effective contraceptive option than SARC. Therefore, women switching from current SARC use to LNG-IUS 13.5 mg are likely to generate cost savings to third-party health care payers, driven principally by decreased UP-related expenditures and long-term savings in contraceptive costs.

Retrospective analysis of variation in heavy menstrual bleeding treatments by age and underlying cause.

OBJECTIVE: To describe treatment patterns associated with heavy menstrual bleeding (HMB) in US practice. STUDY DESIGN: A retrospective claims-based analysis of organic (ICD-9 codes 218.x, 621.0, 622.7, 219.x, and bleeding disorders) or idiopathic (no underlying condition identified) HMB treatment patterns among newly diagnosed, commercially insured women who were enrolled in a large US health plan. First HMB claim (index date; ICD-9-CM 626.2 and 627.0), second HMB claim within 180 days of index date, and continuous enrollment ≥6 months prior to (pre-index period) and 18 months following (post-index period) index date were required. RESULTS: The database included 13,579 organic and 21,362 idiopathic HMB patients. More organic HMB patients received only one treatment type (64% vs 58%; p < 0.001) or two treatments types (14% vs 11%; p < 0.001) compared to idiopathic HMB patients. During the 18 month post-index period, fewer organic HMB patients had no observed treatment compared to idiopathic HMB patients (21% vs 31%; p < 0.001). The idiopathic cohort had significantly higher rates (p < 0.001) of medication use and endometrial ablation, whereas the organic HMB cohort had a higher rate of hysterectomy (p < 0.001). Women <35 years were more frequently prescribed medical treatments (p ≤ 0.037), while women aged >35 years utilized significantly more surgical approaches (p < 0.001). CONCLUSIONS: Among organic and idiopathic HMB patients, considerable variation was observed in the medications and procedures used to treat HMB. Current treatment pattern awareness may improve HMB management. Future research is needed to understand factors that influence women's treatment choices (including newer medications LNG-IUS and tranexamic acid) and age in relation to child-bearing preference.

Cost burden and treatment patterns associated with management of heavy menstrual bleeding.

OBJECTIVES: This study evaluated the healthcare resource use, work productivity loss, costs, and treatment patterns associated with newly diagnosed idiopathic heavy menstrual bleeding (HMB) using a large employer database. METHODS: Medical and pharmacy claims (1998-2009) from 55 self-insured U.S. companies were analyzed. Women aged 18-52 years with ≥2 HMB claims (ICD-9 626.2, 627.0) and continuously enrolled for ≥6 months before the first claim were matched 1:1 with controls. Exclusion criteria were cancer, pregnancy, and infertility; HMB-related uterine conditions; endometrial ablation; hysterectomy; anticoagulant medications; and other known HMB causes. All-cause healthcare resource use and costs were compared between the HMB and control cohorts using statistical methods accounting for matched study design. Treatment patterns were examined for HMB subjects. RESULTS: HMB and control cohorts (n=29,842 in both) were matched and balanced in baseline characteristics and costs. During follow-up, HMB subjects had significantly higher all-cause resource use than did control subjects: hospitalization incidence rate ratio (IRR)=2.70 (95% confidence interval [CI] 2.62-2.79); emergency room visits IRR=1.35 (95% CI 1.31-1.38); outpatient visits IRR=1.29 (95% CI 1.29-1.30). Average annualized all-cause costs were also higher for HMB subjects than controls (mean difference $2,607, p<0.001). Costs associated with HMB claims represented 50% ($1,313) of the all-cause cost difference. Of HMB subjects, 63.2% underwent surgical treatment as initial therapy. CONCLUSIONS: In this large matched-cohort study, an idiopathic diagnosis of HMB was associated with high rates of surgical intervention and increased healthcare resource use and costs.