Impact of a Health Management Program on Healthcare Outcomes among Patients on Augmentation Therapy for Alpha 1-Antitrypsin Deficiency: An Insurance Claims Analysis.

INTRODUCTION: Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct®; PD). OBJECTIVES: This study compared clinical and economic outcomes between patients with and without PD program participation. METHODS: This retrospective study included commercial and Medicare Advantage health insurance plan members with ≥ 1 claim with diagnosis codes for COPD and ≥ 1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin® or Prolastin®-C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts. RESULTS: The study sample comprised 445 patients (n = 213 in PD cohort; n = 232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations. CONCLUSIONS: These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy. FUNDING: Grifols Shared Services of North America, Inc.

Inhaled alpha 1-antitrypsin: gauging patient interest in a new treatment.

BACKGROUND: Given the high cost of plasma derived intravenous alpha 1-antitrypsin (AAT), a more efficient method of delivery to the lungs is desirable. Inhaled AAT has been shown feasible for the treatment of alpha 1-antitrypsin deficiency (AATD) and is currently in clinical trials. To better understand patient preferences about possible inhaled AAT therapy, a survey was conducted to explore patient attitudes. METHODS: We conducted an email based survey of patients in the Alpha-1 Foundation Research Registry with AATD on intravenous AAT replacement. Respondents were asked to rate their interest in hypothetical nebulized or dry powder inhaled AAT. RESULTS: Respondents reported high levels of interest in both dried powder inhaler and nebulizer delivered inhaled AAT. The interest in dried powder inhaled was higher than interest in nebulized AAT (71% vs 64%, p = 0.0001). The interest in dried powder inhaled AAT was particularly high in respondents currently on bronchodilator therapy (p = 0.0053). Patients were just as likely to use or not use the product if it required 20% more out of pocket cost. CONCLUSIONS: There is a high level of patient interest in the development of a commercially available inhaled AAT replacement product.

A review of augmentation therapy for alpha-1 antitrypsin deficiency.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. Specific therapy for lung-affected individuals with AATD is augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT). Augmentation therapy was first approved by the United States Food and Drug Administration (FDA) in 1987 for emphysema associated with severe AATD and today, six augmentation therapy preparations, all of which derive from pooled human plasma, have received FDA approval. AREAS COVERED: This paper reviews augmentation therapy for AATD, including the various available commercial preparations, their processing and biochemical differences, evidence regarding biochemical and clinical efficacy, patterns of clinical use, adverse effect profiles, cost-effectiveness and potential uses in conditions other than emphysema associated with AATD. Novel and emerging strategies for treating AATD are briefly discussed next, including alternative dosing and administration strategies, recombinant preparations, small molecule inhibitors of neutrophil elastase and of AAT polymerization, autophagy-enhancing drugs and gene therapy approaches. EXPERT OPINION: We conclude with a discussion of our approach to managing patients with AATD and use of augmentation therapy.

Emerging drugs for alpha-1-antitrypsin deficiency.

IMPORTANCE OF THE FIELD: Alpha-1-antitrypsin (A1AT) deficiency is a common genetic condition that predisposes individuals to the development of chronic obstructive pulmonary disease (COPD) as a direct result of damage caused to the lung by proteolytic enzymes released by migrating neutrophils. The lack of A1AT fails to control these enzymes and in the most common genetic deficiency (Pi Z) is due to accumulation of A1AT in the liver as a result of polymer formation. There is no specific treatment for COPD but understanding the pathophysiology of the disease in A1AT deficiency has led to strategies being used or developed to prevent the lung and liver disease. These strategies may have benefits beyond A1AT deficiency. AREAS COVERED IN THIS REVIEW: The review covers the history of discovery of the nature and role of A1AT deficiency with particular emphasis on the pathophysiology of the lung disease. Evidence for the role of current therapies is provided together with data of preliminary or experimental strategies that are under development. WHAT THE READER WILL GAIN: The reader will gain insight into the role of proteinases in the pathophysiology of COPD with particular reference to A1AT deficiency, which is the only human model of the disease. Current evidence of the efficacy of augmentation is provided together with new ways of readdressing the balance between neutrophil proteinases and natural or synthetic inhibitors or repairing lung damage. TAKE HOME MESSAGE: A1AT deficiency is a good model to investigate the role of inflammation and proteolytic enzymes in the pathophysiology of COPD. Augmentation therapy is expensive but restores the deficiency to normal and current evidence suggests this ameliorates progression of the disease. Understanding the mechanisms involved has led to the development of newer strategies to protect the lung and liver from the development of disease but efficacy and safety concerns require careful introduction of these strategies. Although the condition is relatively common in the Northern hemisphere, the ability to deliver conventional Phase III clinical trials with lung physiology as the primary outcome will be limited by the sensitivity of the tests and number of patients required.

alpha1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note.

The use of IV augmentation therapy with plasma-derived alpha1-antitrypsin (AAT) has become the standard of care for the treatment of pulmonary disease associated with the severe genetic deficiency of AAT. The Medical and Scientific Advisory Committee of the Alpha-1 Foundation has become aware that physicians are prescribing this expensive blood product for the treatment of individuals with a single abnormal AAT gene, primarily the PI*MZ genotype. We are aware of no evidence that such therapy is effective in this patient population. The most important therapeutic interventions in such patients remain smoking cessation and elimination of other risk factors for lung disease. This commentary discusses the treatment of AAT deficiency and the concerns regarding treatment of PI*MZ individuals. We conclude that clinicians should avoid prescribing augmentation therapy for this heterozygote population.

Aralast: a new alpha1-protease inhibitor for treatment of alpha-antitrypsin deficiency.

OBJECTIVE: To review the epidemiology, pathogenesis, and management of patients with alpha-antitrypsin (AAT) deficiency syndrome and compare Aralast with Prolastin, 2 of the 3 available human plasma-derived AAT agents. DATA SOURCES: Articles were identified using a MEDLINE (1966-September 2005) search with MESH headings that included alpha-antitrypsin and emphysema. STUDY SELECTION AND DATA EXTRACTION: All papers from peer-reviewed journals on the laboratory or clinical efficacy of plasma-derived AAT (eg, Prolastin, Aralast) for patients with this autosomal recessive disorder were reviewed. DATA SYNTHESIS: Clinical trials found that AAT augmentation prevents progression of AAT-deficient emphysema and thus its associated morbidity and mortality. Treatment with Aralast has been shown to be safe and well tolerated, with a low incidence of mild to moderate adverse events. Pharmacoeconomics studies of AAT augmentation demonstrated that the use of Aralast was cost-effective as lifelong augmentation therapy for AAT-deficient emphysema. CONCLUSIONS: Because of its effectiveness and extra safety measure compared with Prolastin, Aralast should be recommended for formulary inclusion.

Augmentation therapy for alpha(1)-antitrypsin deficiency.

alpha(1)-Antitrypsin (AAT) deficiency is a common but under-recognised condition. Since its first description by Laurell and Eriksson in 1963, significant advances have been made in understanding the genetics, physiology and pathophysiology of this condition. The intravenous administration of purified AAT to AAT-deficient individuals has been shown to confer biochemical efficacy by raising the serum AAT level above an epidemiologically established 'protective threshold' while preserving the biochemical properties and functional capacity of the protease inhibitor. Although the lack of a large randomised controlled trial to date has precluded the definitive demonstration of clinical efficacy of intravenous AAT augmentation therapy, substantial evidence supporting its use in AAT-deficient individuals with moderate airflow obstruction has accumulated. For example, both large observational studies comparing rates of forced expiratory volume decline among recipients of augmentation therapy versus non-recipients have shown slower rates of decline among augmentation therapy recipients, especially those with moderately severe airflow obstruction. Also, some evidence suggests that use of augmentation therapy confers an anti-inflammatory effect. For example, a web-based survey suggested that recipients of augmentation therapy experienced fewer respiratory infections than non-recipients. Despite its high cost, intravenous AAT augmentation therapy remains the only US FDA-approved treatment option for patients with AAT deficiency. Research into new and evolving treatments is currently underway.

Tailored pharmacokinetic dosing allows self-administration and reduces the cost of IV augmentation therapy with human alpha(1)-antitrypsin.

OBJECTIVE: Severe alpha(1)-Antitrypsin (AAT) deficiency (PiZZ) predisposes to the development of emphysema. Intravenous augmentation therapy with purified human AAT has been available since 1988. The dosage has varied from 60 mg/kg body weight once weekly to 250 mg/kg once monthly. We have found the dosage of 120 mg/kg every 2 weeks to be the most convenient for the patients. The treatment is very expensive. The objective of this investigation was to study whether tailored pharmacokinetic dosing of human AAT allows self-administration and reduces the total annual dose and cost of intravenous augmentation therapy. METHODS: Five PiZZ individuals receiving purified human AAT at a dose of 120 mg/kg every 2 weeks were included in the study. Three patients had a percutaneous and one patient had a subcutaneous intravenous injection port system. After a 4-week interruption of the treatment an ordinary dose of 120 mg/kg human AAT was infused. Plasma AAT levels were determined preinfusion, postinfusion, and once daily for 10-14 days. The pharmacokinetic parameters of exogenous AAT were calculated for each patient. Based on these, individual dosage schemes were designed by computer simulation. The patients were treated with the new dose twice weekly for 4 weeks, and plasma AAT was determined immediately before the last two infusions. RESULTS: At a dose of 1 or 2 g twice weekly the median annual consumption of human AAT was reduced from 286 to 156 g/patient. The trough plasma AAT level was maintained above 0.70 g/l, which is considered as protective. The three patients who had an implanted percutaneous venous port system learned to administer the treatment by themselves at home. The other two patients were treated at home by the district nurse. CONCLUSIONS: The results of our study indicate that tailored pharmacokinetic dosing of human AAT reduces the total annual dose and cost of IV augmentation therapy. In addition, this dosing facilitates self-administration of AAT and allows treatment at home.

The direct medical costs of alpha(1)-antitrypsin deficiency.

BACKGROUND: For individuals with emphysema because of severe alpha(1)-antitrypsin deficiency, specific therapy called IV augmentation therapy has been available since 1989. Such therapy consists of IV infusion of pooled human plasma alpha(1)-antiprotease. METHODS: To assess the direct medical costs of having alpha(1)-antitrypsin deficiency, the current study surveyed members of the Alpha One Foundation Registry for Individuals With alpha(1)-Antitrypsin Deficiency regarding their annual expenditures for treatment of this disease. Data regarding demographic features, alpha(1)-antitrypsin status, and health-resource utilization were collected from a self-administered questionnaire. Respondents were asked to provide total health-care expenditures, but costs by specific items of care (eg, drugs, physician visits, etc) were not available. RESULTS: Mean annual cost estimates were higher for PI*ZZ-phenotype individuals ($30,948, n = 292) than for non-PI*ZZ-phenotype individuals ($20,673, n = 53; p = 0.049). Among PI*ZZ-phenotype individuals, self-reported costs of health-care services were further analyzed for those 288 individuals whose alpha(1)-antiprotease use status was reported. For the 185 current alpha(1)-antiprotease users, the mean annual cost was $40,123 (median, $36,000). CONCLUSIONS: Annual health-care expenditures by individuals with alpha(1)-antitrypsin deficiency are very high, whether or not they are currently receiving augmentation therapy. Augmentation therapy adds substantial costs, especially for heavier individuals who are receiving weekly infusions.

Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis.

STUDY OBJECTIVES: Assess cost effectiveness for providing alpha(1)-antitrypsin (alpha(1)-AT) replacement therapy to individuals with severe COPD and alpha(1)-AT deficiency. MATERIALS AND METHODS: The electronic databases MEDLINE and EMBASE were searched, and relevant bibliographies were reviewed. Effect size, defined as the absolute risk difference between treated and untreated groups, was taken from the highest level of supporting evidence. The cost for providing alpha(1)-AT replacement therapy was analyzed from a payer perspective and was based on Medicare reimbursement rates. Effect size and costs were varied. The year of life saved was discounted up to 7%. RESULTS: The incremental cost per year of life saved for alpha(1)-AT replacement therapy (60 mg/kg/wk IV) in a 70-kg subject with severe alpha(1)-AT deficiency and an FEV(1) < 50% of predicted based on the National Institutes of Health (NIH) Registry mortality rate data is $13,971. The incremental cost depends substantially on the mortality rate reduction. When the effect size is altered from 10 to 70%, with the cost fixed at $52,000, the incremental cost per year of life saved ranges from $152,941 to $7,330. When effect size is 55% (as in the NIH Registry) but costs are increased almost 300%, from $52,000 to $150,000 per year, then the incremental cost per year of life saved increases from $13,971 to $40,301. CONCLUSION: No randomized, placebo-controlled trials are available to assess mortality rate reduction with alpha(1)-AT replacement therapy. The best currently available data are observational, from the NIH Registry. Based on these data, alpha(1)-AT replacement therapy is cost-effective in individuals who have severe alpha(1)-AT deficiency and severe COPD.