Systematic Literature Review of the Burden of Disease and Treatment for Transfusion-dependent ß-Thalassemia.

PURPOSE: ß-Thalassemia is an inherited blood disorder characterized by reduced or no production of adult hemoglobin. Systematic identification of the burden of ß-thalassemia with contemporary treatments is lacking in published literature. Thus, a gap exists in understanding the baseline burden on which to assess future treatments. Therefore, a systematic literature review (SLR) was performed to assess management and outcomes in patients with transfusion-dependent ß-thalassemia (TDT) who received long-term transfusion regimens. METHODS: Searches of MEDLINE, EMBASE, and 5 conference websites were conducted to identify clinical-practice studies in Italy, France, Germany, Greece, the United States, and the United Kingdom, published since January 2007. The review found 135 articles meeting the SLR criteria. FINDINGS: Among patients carrying 2 ß-thalassemia mutations, 64%-89% underwent regular transfusions at intervals of between 2 and 4 weeks. Transfusion-associated complications that were reported included iron overload, transfusion reactions, alloimmunization, and infections. Analyses of 42, 25, and 73 studies reporting liver iron concentration (median, 8.5 mg/g of dry weight [dw]; interquartile range [IQR], 4.5-11.0 mg/g dw), cardiac T2* magnetic resonance imaging (median, 27.4 ms; IQR, 26.0-30.2 ms), and serum ferritin (median, 1465.0 ng/mL; IQR, 1238.2-1797.0 ng/mL), respectively, showed wide ranges in iron levels and a general trend toward improved iron control in recent years. Adverse transfusion reactions and alloimmunization were reported in ~50% and 10%-20% in patients, respectively. Rates of transfusion-transmitted infections were highly variable by study but were lower in more recent cohorts. Complications stemming from iron overload and underlying disease captured in this SLR included cardiac disease, liver disease, and endocrine and musculoskeletal disorders. Approximately 10% of patients were diagnosed with heart failure, with rates ranging from 2.9% to 20.9% across 6 studies. Other significant complications reported with ß-thalassemia included pain (25%-69%), psychiatric disorders (25%-30%), and reduced health-related quality of life. Despite substantial improvements in survival, patients with TDT remained at an increased risk for early mortality. IMPLICATIONS: Consistent with improvements in transfusion practices and iron monitoring and management, outcomes in patients with TDT have improved. However, iron overload and disease-associated complications remain a challenge in this population. This review supports the burden of disease affecting patients with ß-thalassemia and provides a baseline health status against which to assess future improvements in care.

Health state utilities associated with treatment for transfusion-dependent ß-thalassemia.

OBJECTIVES: Transfusion-dependent ß-thalassemia (TDT) is a genetic disease that affects production of red blood cells. Conventional treatment involves regular red blood cell transfusions and iron chelation, which has a substantial impact on quality of life. While potentially curative, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with risk of complications, including graft-versus-host disease (GvHD). Gene addition therapy, a novel treatment approach, involves autologous transplantation of the patient's own genetically modified hematopoietic stem cells. The purpose of this study was to estimate utilities associated with treatment approaches for TDT. METHODS: General population respondents in England valued eight health state vignettes (developed with clinician, patient, and parent input) in time trade-off interviews. RESULTS: A total of 207 participants completed interviews (49.8% female; mean age = 43.2 years). Mean (SD) utilities for the pre-transplant health states were 0.73 (0.25) with oral chelation and 0.63 (0.32) with subcutaneous chelation. Mean utilities for the transplant year were 0.62 (0.35) for gene addition therapy, 0.47 (0.39) for allo-HSCT, and 0.39 (0.39) for allo-HSCT with acute GvHD. Post-transplant utilities were 0.93 (0.15) for transfusion independent, 0.75 (0.25) for 60% transfusion reduction, and 0.51 (0.38) for chronic GvHD. Acute and chronic GvHD were associated with significant disutility (acute = - 0.09, p < 0.0001; chronic = - 0.42, p < 0.0001). CONCLUSIONS: Utilities followed expected patterns, with logical differences between treatment options for TDT and substantially greater utility for transfusion independence than for ongoing treatment involving transfusion and chelation. These utilities may be useful in cost-utility models estimating the value of treatments for TDT.

The Early Engagement Model in Product Development: Linking "Proof of Concept" to "Proof of Medical Value".

In a rapidly changing health care environment, it is more important than ever that pharmaceutical manufacturers improve the quality and efficiency of their research and development efforts in order to help ensure the right drug gets to the right patient at the right time. The evolving role of the Medical Affairs, Health Economics & Outcomes Research (HEOR) and other functions engaged in evidence generation within the pharmaceutical industry is leading to earlier involvement in the clinical development process so that the proof of concept for new therapies can be more strongly linked to the proof of medical value. In this article, the authors outline key components of an Early Engagement Model that connects the proof of concept to proof of medical value through a systematic approach linking molecular profile with early insights on disease, unmet needs, stakeholder requirements, and patient-centric differentiation.

A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States.

Acetaminophen is a commonly-used analgesic in the US and, at doses of more than 4 g/day, can lead to serious hepatotoxicity. Recent FDA and CMS decisions serve to limit and monitor exposure to high-dose acetaminophen. This literature review aims to describe the exposure to and consequences of high-dose acetaminophen among chronic pain patients in the US. Each year in the US, approximately 6% of adults are prescribed acetaminophen doses of more than 4 g/day and 30,000 patients are hospitalized for acetaminophen toxicity. Up to half of acetaminophen overdoses are unintentional, largely related to opioid-acetaminophen combinations and attempts to achieve better symptom relief. Liver injury occurs in 17% of adults with unintentional acetaminophen overdose.

Outpatient RSV lower respiratory infections among high-risk infants and other pediatric populations.

OBJECTIVE: To identify the frequency of outpatient, non-hospitalized visits for respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) among children and high-risk infants. STUDY DESIGN: Published studies that reported population-based rates of outpatient RSV illness were reviewed. In addition, we conducted a retrospective cohort study from a national claims database including preterm and full term infants born between April 2004 and April 2006 <6 months of age and continuously enrolled through their first RSV season. RESULTS: In the selected published studies, rates of outpatient RSV LRI were highest among infants and young children (ranging from 6.9 to 11 per 1,000 children age 1-4 years to 157.5 to 252.0 per 1,000 children age <1 year). In the cohort study, rates of outpatient RSV LRI among preterm infants

Value of biologic therapy: a forecasting model in three disease areas.

OBJECTIVE: Forecast the return on investment (ROI) for advances in biologic therapies in years 2015 and 2030, based upon impact on disease prevalence, morbidity, and mortality for asthma, diabetes, and colorectal cancer. METHODS: A deterministic, spreadsheet-based, forecasting model was developed based on trends in demographics and disease epidemiology. 'Return' was defined as reductions in disease burden (prevalence, morbidity, mortality) translated into monetary terms; 'investment' was defined as the incremental costs of biologic therapy advances. Data on disease prevalence, morbidity, mortality, and associated costs were obtained from government survey statistics or published literature. Expected impact of advances in biologic therapies was based on expert opinion. Gains in quality-adjusted life years (QALYs) were valued at $100,000 per QALY. RESULTS: The base case analysis, in which reductions in disease prevalence and mortality predicted by the expert panel are not considered, shows the resulting ROIs remain positive for asthma and diabetes but fall below $1 for colorectal cancer. Analysis involving expert panel predictions indicated positive ROI results for all three diseases at both time points, ranging from $207 for each incremental dollar spent on biologic therapies to treat asthma in 2030, to $4 for each incremental dollar spent on biologic therapies to treat colorectal cancer in 2015. If QALYs are not considered, the resulting ROIs remain positive for all three diseases at both time points. CONCLUSIONS: Society may expect substantial returns from investments in innovative biologic therapies. These benefits are most likely to be realized in an environment of appropriate use of new molecules. LIMITATIONS: The potential variance between forecasted (from expert opinion) and actual future health outcomes could be significant. Similarly, the forecasted growth in use of biologic therapies relied upon unvalidated market forecasts.

Evaluation of resource utilization and cost burden before and after an employer-based migraine education program.

OBJECTIVES: Study objectives were to determine the impact of migraine and severe headache on employer burden, resource utilization, and workplace productivity before and after a migraine education program; estimate the associated costs in an employed sample; and evaluate whether a migraine management program can help manage costs. METHODS: Employees of three US companies were informed of a company-specific web site with information regarding the study as well as a validated migraine screening questionnaire. Employees who screened positive for migraine completed a baseline survey examining migraine frequency and severity, Migraine Disability Assessment (MIDAS) grade, medical resource utilization, and impact on workplace productivity. After the baseline survey, employees received three print packets and six e-mailed newsletters of migraine management educational materials. Six months after the last mailing, participants completed a follow-up survey. Participants were stratified by MIDAS grade and prevention needs status. Direct and indirect migraine-related costs were estimated and differences between baseline and follow-up survey results were analyzed. RESULTS: Indirect costs and measures of migraine impact improved after the educational program. Three-month indirect costs of migraine decreased 34.5% and total costs decreased 14.7% after the educational program. CONCLUSION: Migraine management programs, including screening questionnaires and educational initiatives, may potentially help reduce the employer cost burden due to improvements in their employees' disability associated with migraine headache.

Can managed care organizations partner with manufacturers for comparative effectiveness research?

OBJECTIVE: To describe 2 published pragmatic or practical clinical trials (PCTs) as case studies illustrating successful partnerships between managed care organizations (MCOs) and pharmaceutical manufacturers. STUDY DESIGN: In today's environment, there is increasing concern about the comparative effectiveness of medical interventions. Various opinion leaders and stakeholders lament the dearth of such evidence and are calling for the public and private sectors to invest up to billions of dollars to create better comparative evidence. METHODS: We selected 2 PCTs conducted at different points in the drug life cycle to highlight strengths, limitations, and policy implications. The phase IV study compared fluoxetine hydrochloride vs 2 generic tricyclic antidepressants in selected primary care clinics of a health maintenance organization from 1992 through 1994. The phase IIIb study compared daily budesonide via dry powder inhaler vs triamcinolone acetonide metered-dose inhaler in adult patients with persistent asthma in 25 MCOs from 1995 through 1998. RESULTS: Both PCTs were successfully sponsored and funded by pharmaceutical manufacturers in collaboration with MCOs and provided potentially useful evidence of real-world effectiveness and evidence of value to healthcare decision makers. CONCLUSIONS: Industry-sponsored PCTs in managed care are feasible when manufacturer and MCO incentives align and can provide real-world evidence of comparative effectiveness and value for money. These trials can be conducted successfully in the phase IIIb and phase IV environments.

Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

OBJECTIVE: To compare the prevalence of cardiovascular diseases and their risk factors between patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and control subjects. METHODS: Data for patients continuously enrolled in an integrated outcomes database between January 1, 2001, and December 31, 2002, with International Classification of Diseases, 9th Revision codes of 714.x (RA), 696.0 (PsA), or 720.0 (AS) were evaluated in this cross-sectional comparative study. Control groups were established for each patient group (1:4 ratio) by matching on the basis of age, sex, geographic region, and length of time in plan. Age- and sex-adjusted prevalence of cardiovascular comorbidities and risk factors were calculated; the prevalence ratio of the comorbidities and risk factors for the patient groups compared with the control population were estimated. Use of selected cardiovascular medications was also compared between patient and control groups. RESULTS: The RA, PsA, and AS cohorts comprised 28,208, 3066, and 1843 patients, respectively. The prevalence ratio of ischemic heart disease (1.5, 1.3, 1.2), atherosclerosis (1.9, 1.4, 1.5), peripheral vascular disease (2.4, 1.6, 1.6), congestive heart failure (2.0, 1.5, 1.8), cerebrovascular disease (1.6, 1.3, 1.7), type II diabetes (1.4, 1.5, 1.2), hyperlipidemia (1.2, 1.2, 1.2), and hypertension (1.3, 1.3, 1.3) were higher in patients than controls. For RA, PsA, and AS, use of angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, nitrates/vasodilators, anticoagulants, and antihyperlipidemia agents was significantly higher in patients than controls. CONCLUSION: Cardiovascular diseases and their risk factors were more common in patients with RA, PsA, and AS than in matched controls.

Estimating costs of care for patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: This study examines the resource use patterns and costs of care for patients with incident metastatic colorectal cancer (mCRC) based on analyses of retrospective claims data from selected health plans in the United States. PATIENTS AND METHODS: A case-control analysis was performed using claims from years 1998-2004. Incident mCRC cases were identified based on evidence of a colorectal cancer diagnosis and a metastatic disease diagnosis. Incident mCRC cases could have no other evidence of cancer in the 1-year period before the date of their first mCRC diagnosis. Cases were matched to non-mCRC controls based on age, sex, geographic region, and duration of plan enrollment. Costs were evaluated by phase of disease: diagnosis, treatment, or death phases. Ordinary least squares regressions were performed to evaluate impact of covariates in each phase. RESULTS: Total costs in the follow-up period averaged $97,031 more for mCRC cases than for controls. The main cost drivers for mCRC were hospitalizations ($37,369) and specialist visits ($34,582), which included chemotherapy administration. Approximately 40% of the 672 patients with mCRC who qualified for the phase analysis were identified with a fatal event during follow-up. Monthly costs were similar in the diagnostic phase ($12,205) and death phase ($12,328), but were significantly lower in the treatment phase ($4722). Both mean/median monthly costs increased over time during the study period, regardless of disease phase. CONCLUSION: The economic burden of mCRC is substantial for patients with commercial health plans in the United States, and costs of care have increased substantially in recent years.

The return on investment in health care: from 1980 to 2000.

OBJECTIVE: To estimate the return on US investment (ROI) in overall health as well as four specific conditions. METHODS: The study utilized three distinct approaches to "triangulate" the evidence as related to ROI in health care: 1) an estimation of the average ROI in additional health-care service expenditures in the United States for the year 2000 compared with the year 1980, based on US summaries of health expenditures and health outcomes; 2) an estimate of the ROI in Medicare services for the period from 1985 to 2000 for treatment of heart attack, stroke, type 2 diabetes, and breast cancer, based on National Long-term Care Survey data and Medicare claims; and 3) an estimate of the ROI for selected major treatment innovations for the same four conditions during the period from 1975 to 2000. RESULTS: We calculated that each additional dollar spent on overall health-care services produced health gains valued at Dollars 1.55 to Dollars 1.94 under our base case assumptions. The return on health gains associated with treatment for heart attack, stroke, type 2 diabetes, and breast cancer were Dollars 1.10, Dollars 1.49, Dollars 1.55, and Dollars 4.80, respectively, for every additional dollar spent by Medicare. The ROI for specific treatment innovations ranged from both savings in treatment costs and gains in health to gains in health valued at Dollars 1.12 to Dollars 38.00 for every additional dollar spent. CONCLUSION: The value of improved health in the US population in 2000 compared with 1980 significantly outweighs the additional health-care expenditures in 2000 compared with 1980.

Patient satisfaction with budesonide Turbuhaler versus triamcinolone acetonide administered via pressurized metered-dose inhaler in a managed care setting.

Dissatisfaction with medication may negatively affect compliance and thus the effectiveness of the treatment. However, no prospective well-controlled studies have assessed the relative patient satisfaction with competing inhaled corticosteroids in a real-life setting. The objective of the current study was to compare the relative patient satisfaction with budesonide inhalation powder administered via Turbuhaler (AstraZeneca LP, Wilmington, DE) (200 to 1600 microg/d using one of 3 dosing strengths: 100, 200, or 400 microg per inhalation) and triamcinolone acetonide administered via pressurized metered-dose inhaler (200 to 1600 microg/d) among persons treated in managed care settings. A total of 945 subjects 18 years of age or older diagnosed with asthma and enrolled in 25 managed care organizations participated in this prospective, randomized, open-label, parallel-group, 12-month study. As part of the study, subjects completed a self-administered, 17-item patient satisfaction questionnaire that addressed 4 domains: side effects, knowledge/ease of use, convenience, and overall satisfaction. Questionnaire reliability was assessed using Cronbach's alpha, and validity was examined by correlating subscale scores with symptom-free days and Medical Outcomes Study 36-Item Short-Form questionnaire and Asthma Quality of Life Questionnaire scores. The satisfaction questionnaire also included a previously validated section addressing patient compliance. Patients receiving budesonide had significantly higher scores for all four satisfaction subscales throughout the study period than did those receiving triamcinolone acetonide. Similarly, compliance scores were consistently higher for the budesonide group. The difference between the treatment groups in overall satisfaction scores at the end of the study was clinically meaningful. Patients treated with budesonide were significantly more satisfied and compliant with their inhaled corticosteroid regimen compared with patients treated with triamcinolone acetonide.

A respiratory therapist-directed protocol for managing inpatients with asthma and COPD incorporating a long-acting bronchodilator.

This prospective study was designed to determine whether incorporating formoterol into a standardized respiratory therapist-directed protocol for administering bronchodilators to hospitalized patients with obstructive airway disease would reduce health care resource use and provide a safety advantage. All patients admitted to Washington Hospital Center with asthma and chronic obstructive pulmonary disease (CODP) are administered bronchodilators under a standardized respiratory therapist-directed protocol. Formoterol was the primary bronchodilator for the intervention period from January through March 2002, with levalbuterol, albuterol, and ipratropium available as needed. Results for the intervention period were compared against two historical control periods. From January through March 2000, the bronchodilators in the protocol were albuterol and ipratropium, and from January through March 2001 levalbuterol, albuterol, and ipratropium were available. Health care resource use was determined by the number of bronchodilator treatments administered per admission. Costs (adjusted to 2002 dollars) for supplies, therapist time, and drugs were calculated for the three time periods. Adverse events related to bronchodilator administration were recorded in a standardized manner for all three time periods. Bronchodilator treatments per admission, respiratory therapist visits per admission, and time spent per admission, and cost per bronchodilator treatment significantly decreased in 2002. Significantly fewer adverse events related to bronchodilator treatments were reported in 2002 than 2000. The addition of formoterol to a respiratory therapist-directed protocol for administering bronchodilators reduced health care resource use and adverse events for patients with asthma and COPD.

Economic impact of respiratory syncytial virus-related illness in the US: an analysis of national databases.

OBJECTIVE: To determine the impact of respiratory syncytial virus (RSV) infection on healthcare resource use and costs in the US from the third-party payer perspective. DESIGN: The study retrospectively analysed cross-sectional medical encounter data from three federally funded databases that comprise nationally representative samples of hospital inpatient stays, physician office visits and visits to hospital outpatient departments and emergency rooms. METHODS: Identification of RSV infection-related medical encounters was based on the occurrence of RSV-specific International Classification of Diseases (9th Edition)-Clinical Modification diagnosis codes (079.6, 466.11, 480.1) as principal discharge diagnoses or the assumption that 10-15% of all otitis media visits were due to RSV infection. Outpatient drug costs were estimated based on average wholesale price, and physician fees and test/procedure costs were estimated based on prevailing national fees. Inpatient costs were estimated from total billed charges using a cost-to-charge ratio of 0.53. RESULTS: In 2000, nearly 98% of RSV infection-related hospitalisations occurred in children <5 years old. There were approximately 86,000 hospitalisations, 1.7 million office visits, 402 000 emergency room visits and 236,000 hospital outpatient visits for children <5 years old that were attributable to RSV infection. Total annual direct medical costs for all RSV infection-related hospitalisations ($US394 million) and other medical encounters ($US258 million) for children <5 years old were estimated at $US652 million in 2000. Otitis media was a major cost driver for physician visits. RSV infection-related hospitalisations increased from 1993 to 2000, but average costs per hospitalisation were relatively stable. CONCLUSION: Treatment of RSV infection-related illness represents a significant healthcare burden in the US. The economic impact of ambulatory care for RSV infection-related illness could be as important as that for RSV infection-related hospitalisation.

Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes.

BACKGROUND: Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. RESULTS: A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.