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(Chest. 2000;117:875-880.)
© 2000 American College of Chest Physicians

Should Health-Care Systems Pay for Replacement Therapy in Patients With {alpha}1-Antitrypsin Deficiency?*

A Critical Review and Cost-Effectiveness Analysis

Stephan A. Alkins, MD and Patrick O’Malley, MD, MPH

* From the Pulmonary and Critical Care Medicine Service (Dr. Alkins) and the Department of Internal Medicine (Dr. O’Malley), Walter Reed Army Medical Center, Washington, DC.

Correspondence to: Stephan Alkins, MD, Landstuhl Regional Medical Center, CMR 402, Box 2205, APO, AE 09180


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
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 FEV1 < 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.

Key Words: {alpha}1-antitrypsin • cost-effectiveness • cost-benefit analysis • drug therapy • lung diseases, obstructive


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
{alpha}1 -antitrypsin ({alpha}1-AT) is a serum protease inhibitor that protects against neutrophil elastase in the lower respiratory tract. {alpha}1-AT deficiency, first described by Laurell and Eriksson,1 is associated with the development of premature emphysema that typically occurs in the third to fourth decades of life.2 This autosomal codominant disorder is thought to be responsible for approximately 2% of all cases of emphysema in the United States.3

Replacement therapy with pooled human {alpha}1-AT is being used to treat subjects with {alpha}1-AT deficiency. While infusion of {alpha}1-AT is safe4 5 6 7 and has been approved by the Food and Drug Administration for replacement therapy, the benefits of this therapy have never been definitively proven. Observational studies have suggested that in patients with at least moderate airway obstruction, replacement therapy impedes the decline in FEV1.8 9 10

Only one study has assessed the impact of replacement therapy on mortality.10 In that study, the 5-year mortality rate in those subjects with an initial FEV1 < 50% ranged from 33% in the untreated to 15% in the treated group (p < 0.001).

The cost for providing augmentation therapy with human pooled {alpha}1-AT is expensive, approximately $52,000 per year for a 70-kg patient. While this therapy seems to abate the accelerated annual FEV1 decline and to improve the mortality rate, is it cost-effective? We analyzed the cost-effectiveness of this therapy from a payer perspective based on the best evidence available on replacement therapy in individuals with severe {alpha}1-AT deficiency.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix 1
 References
 
We searched the electronic databases MEDLINE and EMBASE between 1980 and December 1998 using the following terms: alpha 1-antitrypsin deficiency, alpha 1-antitrypsin replacement therapy, efficacy, cost-effectiveness, mortality, therapeutic use, pharmacokinetics, administration, and dosage. Bibliographies of relevant articles also were reviewed.

The effect size for the economic analysis was taken from the study with the highest level of supporting evidence that included the mortality outcomes, according to the conventional hierarchy of best designed and least biased evidence.11 12 Effect size was defined as the absolute risk difference between treated and untreated groups. The National Institutes of Health (NIH) Registry was solely utilized in this analysis because it contained the only study identified that included mortality outcomes.10 Other reports document only the change in FEV1 between treated or untreated groups.7 8 9

Life expectancy (LE) was calculated using the declining exponential approximation of life expectancy.13 14 LE was defined as the inverse of mortality (1/m). Mortality was calculated by -(1/t) x ln(survival over time), where t is time, ln is the natural log, and survival is the percentage of subjects alive over time t. Years of life saved was calculated as the LE of treated individuals (LEtreated) minus that of untreated individuals (LEuntreated).

The costs for IV human {alpha}1-AT (Prolastin; Bayer, Inc; West Haven, CT) replacement therapy are calculated from a payer perspective based on Medicare part B reimbursement rates and are reported in 1998 US dollars. This perspective was chosen since Medicare reimbursement is becoming the standard on which health-care delivery systems are basing their reimbursement decision making. The cost estimates were as follows, assuming a weekly 1-h infusion at 60 mg/kg IV. The medication cost is $105 per 500 mg {alpha}1-antitrypsin, and a 70-kg patient would require nine 500-mg vials of {alpha}1-antitrypsin each week. A 1-h infusion of medication can be reimbursed at $54 for the first hour; therefore, a 1-h infusion of 60 mg/kg in a 70-kg patient would cost $945 for {alpha}1-antitrypsin and $54 for the infusion. The yearly total cost would be $51,948, and the 5-year total cost would be approximately $260,000. The optimal timing and dosage of {alpha}1-AT replacement therapy was based on the most recent guidelines issued by the American Thoracic Society, which recommend that {alpha}1-antitrypsin be administered weekly at a dose of 60 mg/kg/wk.15 Overhead costs were not considered since these are not included in Medicare reimbursement payments.

To assess the robustness of our findings, we performed a sensitivity analysis. Several important variables were varied simultaneously to test whether the cost effectiveness was sensitive to a quantity of any variable. The effect size (in this case, absolute risk difference [5-year risk in treated individuals vs. 5-year risk in untreated individuals]) was varied from 5 to 70% to account for the uncertainty associated with using data from an observational study. The cost was varied up to 500% of the Medicare part B reimbursement rates to allow for differences in expenses. The increase in years of life saved by augmentation therapy was compared with and without discount. The years of life saved were discounted to account for the decrease in quality of life associated with weekly infusions. The discount rate was varied between 0% and 7%, as previously described by Weinstein et al.16 This rate was used to account for variables that might affect the validity of the outcomes benefit used in this analysis (health system costs introduced through patient survival and potential costs from therapy complications, for example).17 The sensitivity end points were chosen as reasonably extreme estimates beyond which any costs and effectiveness that are calculated would be unlikely.

Comparisons were made to usual care. This assumed that standard interventions for usual care (bronchodilators or smoking cessation efforts, for instance) also were used in those individuals receiving the intervention. Thus, cost is presented as the incremental cost (or value added) associated with the intervention.18


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix 1
 References
 
The incremental cost in a 70-kg {alpha}1-AT-deficient subject with severe emphysema (FEV1 < 50% of predicted) receiving weekly replacement therapy at 60 mg/kg is $13,971 per year of life saved. The cost-effectiveness of this therapy is calculated by assuming a 55% 5-year mortality rate reduction without discounting the years of life saved (Table 1 ; see also the Appendix).


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  		Table 1. Incremental Cost Per Year of Life Saved*

 
Sensitivity analysis highlights the predominant dependence of this analysis on the degree of mortality rate reduction and, to a lesser degree, on the costs of treatment. If the effect size is only 10% (instead of 55% as seen in the NIH Registry data10 ) and if yearly costs were unchanged ($52,000), then the incremental cost would be $152,941 per year of life saved. Conversely, if the effect size were 70%, then the incremental cost would be $7,330 per year of life saved (Table 1) . If effect size is 55% (as in the NIH data10 ) but the yearly cost increases by nearly 300% to $150,000, then the incremental cost would only increase to $40,301 (Table 1) .

Cost-effectiveness thresholds are value judgments that are used to define scarce societal resources. These thresholds are arbitrary, however, they are used by health-care systems in resource allocation decision making. The cost-effective thresholds used in this analysis are presented only to give context to our findings. A therapy being considered for its cost-effectiveness can be compared to the annual cost of renal dialysis (a therapy that prolongs life, is accepted by the community, and is reimbursed by Medicare). The cost of renal dialysis per year of life saved is approximately $40,000 to $50,000.19 20 If cost-effectiveness is defined as a therapy that costs < $40,000 per year of life saved, then the effect size of {alpha}1-AT replacement therapy would have to be >= 30% (with current therapy cost). The NIH Registry data reported that {alpha}1-AT replacement therapy reduced the 5-year mortality rate by 55% (33 to 15%). This therapy results in an incremental cost that is cheaper than the $40,000 per year of life saved when the annual cost is approximately < $149,000 (see Example 2 in the Appendix). When years of life saved is discounted by 7% and current therapy costs are used, then the effect size of {alpha}1-AT replacement therapy would have to be >= 33% (Table 2 ; see also Appendix) to result in an incremental cost of < $40,000 per year of life saved.


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  		Table 2. Incremental Cost Per Year of Life Saved With Years of Life Saved Discounted 7%*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix 1
 References
 
Given the absence of randomized, placebo-controlled trial data with {alpha}1-AT replacement therapy, and the ethical dilemma of withholding a potentially beneficial treatment in a placebo-controlled study,21 decisions regarding the use of {alpha}1-AT augmentation must be based on the best observational data available. Assuming that the mortality rate reduction associated with {alpha}1-AT replacement therapy in the NIH Registry10 is valid, this cost analysis suggests that {alpha}1-AT replacement is cost-effective for severely deficient patients with severe COPD.

Hay and Robin22 explored the cost-effectiveness of replacement therapy with human {alpha}1-AT before survival data were available and reached similar conclusions. They explored the cost-effectiveness of replacement therapy under a wide variety of assumptions. LE and survival data were adapted from the reported natural history of {alpha}1-AT-deficient subjects and from United States vital statistics. Survival was varied depending on age, sex, and smoking history. In their analysis, the efficacy of therapy was defined as the change in survival, and costs were based on medical care cost estimates in individuals with COPD. They concluded that if {alpha}1-AT replacement therapy had an efficacy of 70%, then the cost per year of life saved would be between $28,00 and $72,000 (depending on patient age, sex, and smoking status). If this therapy were only 30% effective, then the cost per year of life saved would vary between $50,000 and $128,000. The survival advantage in always treated {alpha}1-AT-deficient subjects with an initial FEV1 <= 50% in the NIH Registry10 equates to a 55% efficacy (reduction in 5-year mortality rate from 33 to 15%). Our sensitivity analysis yielded results similar to those of Hay and Robin, with the incremental cost per year of life saved varying between $10,747 and $53,735, with an effect size of 55% when yearly {alpha}1-AT replacement costs vary from $40,000 to $200,000 (Table 1) . This analysis did not address the discounting of costs or quality-of-life changes associated with receiving lifelong IV replacement therapy. While these are limitations, we used a 7% discount rate for the years of life saved, and the findings were not sensitive to this (ie, the treatment was still cost-effective) (Table 2) . It is unlikely that these limitations will affect the overall conclusion that replacement therapy is cost-effective as defined by the usual standards.

Although outcome studies such as the NIH Registry data are crucial in justifying any therapeutic modality, the basic rationale for the use of {alpha}1-AT augmentation is robust. First, severe {alpha}1-AT deficiency causes emphysema. Second, replacement therapy with {alpha}1-AT is known to increase the levels of {alpha}1-AT in serum and epithelial lining fluid.4 23 This increase in protease inhibitor concentration has been presumed to interfere with the progression of emphysema by protecting against neutrophil elastase.

Third, observational cohort studies have demonstrated a slowing of FEV1 decline in those individuals with severe {alpha}1-AT deficiency8 9 10 and improvement in mortality rate10 when treatment is given. These observational studies reported a statistically significant reduction in the annual FEV1 decline in treated subjects whose initial FEV1 levels indicated moderate to severe airway obstruction, compared to that in untreated subjects. Seersholm et al8 reported that treated patients with initial FEV1 levels that are 31 to 65% of predicted had declines of 62 mL/yr compared to 83 mL/yr in the untreated group (p = 0.04). The NIH Registry data similarly described a slower annual decline in FEV1 in treated subjects whose initial FEV1 was 35 to 49% of predicted of 66 mL/yr vs 93 mL/yr in untreated subjects (p = 0.003).10

Survival in patients with {alpha}1-AT deficiency has been shown to vary depending on the initial FEV1 and cigarette use. The median overall survival time is 54 years. The median survival time is 49 years for index patients (those who present with {alpha}1-AT deficiency), 69 years for nonindex patients (those identified by screening), 52 years for smokers, and 67 years for nonsmokers.24 Data in the NIH Registry demonstrated a strong association between survival and {alpha}1-AT treatment, even after controlling for potentially important confounding variables. These data showed that survival improves when partial or continuous {alpha}1-AT replacement therapy is administered to patients with severe {alpha}1-AT deficiency and severe COPD as detected on the initial FEV1 measurement. Continuously treated patients with initial FEV1 levels <= 50% of predicted had a 5-year mortality rate of 15% vs 33% for untreated subjects (p < 0.001).10

The NIH Registry data should be strongly considered given its large study population and good follow-up (84% at 5 years). In addition, the potential bias in this study was conservative. The healthiest subjects (defined by higher initial FEV1 levels, fewer smokers, and greater likelihood of disease being discovered by screening rather than with symptomatic presentations) were more likely to have augmentation therapy withheld, while the treated group, which experienced improved survival, had more severe disease.

While there are no results from randomized, controlled trials that are available to answer the question of whether {alpha}1-AT replacement therapy impacts on FEV1 decline or mortality (such a trial may be completed in the future),25 some have suggested that a randomized, placebo-controlled trial would be unethical.21 The controversy regarding the interpretation of the available studies of {alpha}1-AT replacement is demonstrated by the differing recommendations by the Canadian and American Thoracic Societies. The Canadian Thoracic Society does not recommend utilizing replacement therapy until a multicenter, placebo-controlled trial demonstrates efficacy.15 The guidelines of the American Thoracic Society recommend augmentation therapy only for selected individuals (those > 18 years old with PiZZ, PiZ null, or Pi null null phenotypes with {alpha}1-AT levels < 11 µM/L and abnormal lung function).26

Our incremental cost estimates of {alpha}1-AT replacement, which were based on an ad hoc cost-effectiveness threshold, compare favorably with several other well-accepted therapies. The use of simvastatin for primary prevention of coronary artery disease, for example, has been estimated to cost $195,000 per year of life saved,27 and mammography screening for breast cancer every 18 months in women aged 40 to 49 years has been estimated to cost $105,000 per year of life saved.28 Compared to other commonly accepted practices and therapies, {alpha}1-AT replacement therapy is equivalent to or less expensive than many.

In conclusion, human {alpha}1-AT replacement is safe and appears to retard the accelerated decline of FEV1 and overall mortality rate in a distinct subset of individuals (PiZZ homozygous and severely {alpha}1-antitrypsin deficient, with an initial FEV1 <= 50% of predicted). Lifelong augmentation therapy with {alpha}1-AT in these select individuals is cost-effective by currently accepted standards. Results from a randomized, controlled trial would be needed to fully define whether these observations are accurate or whether they apply to other groups. Such a trial may be unethical or too costly to justify based on the already available data.


   Appendix 1
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
References
 
Tables 1 and 2 show the results of varied costs and treatment effects. The 5-year mortality rate in untreated {alpha}1-AT-deficient patients is 33%. A 5% efficacy would result in a 5-year mortality rate of 31.4%, while a 70% efficacy would result in a 5-year mortality rate of 9.9% (see text for the manner of calculation for LE, mortality, and years of life saved).

Example 1
Assuming an annual {alpha}1-AT replacement therapy cost of $52,000 and a 5-year mortality rate reduction of 55%, {alpha}1-AT replacement therapy with a 55% efficacy will result in a 5-year mortality rate of 14.9%. This translates into an LEtreated value of 31.1 years; a 33% 5-year mortality rate in untreated subjects translates into an LEuntreated value of 12.49 years. So, LEtreated - LEuntreated = 31.1 - 12.49 = 18.61 years saved. Discounting years of life saved by 7% yields 17.31 years. Cost-effectiveness = cost/years of life saved. An annual cost of $52,000 equates with a 5-year cost of $260,000. The cost-effectiveness in this example (without the discounted number of years of life saved) is calculated in the following manner: $260,000/18.61 years = $13,971 per year of life saved. When the years of life saved are discounted by 7%, cost-effectiveness is calculated as $260,000/17.31 years = $15,020 per year of life saved.

Example 2
Assume that the annual {alpha}1-AT replacement therapy costs $148,880, that the 5-year mortality rate reduction is 55%, that the years of life saved is discounted by 7% (17.31 years, as shown in Example 1), and that the annual cost of $148,880 equates with a 5-year cost of $744,000. Then, the cost-effectiveness in this example (without discounted number of years of life saved) is calculated in the following manner: $744,000/18.61 years = $40,000 per year of life saved. When the years of life saved are discounted by 7%, cost-effectiveness is calculated as $744,000/17.31 years = $43,004 per year of life saved.


   Footnotes
 
Abbreviations: {alpha}1-AT = {alpha}1-antitrypsin; LE = life expectancy; LEtreated = life expectancy of treated subjects; LEuntreated = life expectancy of untreated subjects; NIH = National Institutes of Health

The views expressed herein are those of the authors and do not necessarily reflect the views of the U.S. Army or the Department of Defense.

Received for publication December 23, 1998. Accepted for publication September 28, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 

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