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Published ahead of print on February 5, 2003, doi:10.1164/rccm.200209-1035OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1387-1392, (2003)
© 2003 American Thoracic Society

Cost-Effectiveness Analysis of Augmentation Therapy for Severe {alpha}1-Antitrypsin Deficiency

Thomas R. Gildea, Kenneth M. Shermock, Mendel E. Singer and James K. Stoller

Department of Pulmonary and Critical Care Medicine and Pharmacy, the Cleveland Clinic Foundation; Center for Pharmaceutical Outcomes and Policy, The Johns Hopkins Hospital, Baltimore, Maryland; Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Center for Quality Improvement Research, Cleveland Department of Veterans Affairs Medical Center, Institute for Public Health Sciences, MetroHealth Medical Center; Division of Medicine and Section of Respiratory Therapy, Department of Pulmonary and Critical Care Medicine, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to James K. Stoller, M.D., M.S., Department of Pulmonary and Critical Care Medicine, A 90, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: stollej{at}ccf.org


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A Markov-based decision model was created to assess the cost-effectiveness of augmentation therapy (Aug) for severe {alpha}1-antitrypsin deficiency, comparing strategies of: (1) no Aug, (2) Aug for life, and (3) Aug until FEV1 is below 35% predicted. A hypothetical cohort of 46-year-old patients with FEV1 49% predicted was followed over time using Monte Carlo simulation across five possible health states: (1) FEV1 50 to 79% predicted, (2) FEV1 35 to 49% predicted, (3) FEV1 below 35% predicted, (4) status—post-lung transplantation, and (5) dead. Treatment for life yielded 7.19 quality-adjusted life-years (QALYs) and cost $895,243. Treating until FEV1 is below 35% predicted cost $511,930 and produced 6.64 QALYs. "No Aug" cost $92,091 with 4.62 QALYs. The incremental cost-effectiveness ratio was $207,841/QALY for Aug until FEV1 is below 35% predicted and $312,511/QALY for the "Aug for life" strategy. In all sensitivity analyses, the incremental cost-effectiveness ratio for Aug for life exceeded $100,000. The cost of Aug needed to be reduced from $54,765 to $4,900 for the "Aug for life" strategy to be considered cost-effective. We conclude that, compared with other conventionally used health interventions, Aug is relatively less cost-effective. These results should encourage the development of more clinically and cost-effective therapies for {alpha}1-antitrypsin deficiency.

Key Words: cost-effectiveness • {alpha}1-antitrypsin deficiency • decision analysis

{alpha}1-Antitrypsin (AAT) deficiency is a genetic disorder characterized by decreased serum and lung concentrations of {alpha}1-antiprotease, which predisposes to early-onset emphysema. Intravenous augmentation therapy with pooled human plasma {alpha}1-proteinase inhibitor (Prolastin; Bayer, West Haven, CT) is currently the only available Food and Drug Administration–approved specific therapy for AAT deficiency. Augmentation therapy has been shown to have biochemical and possible clinical efficacy in treating patients with severe AAT deficiency (1, 2).

Two cost-effectiveness analyses of augmentation therapy are currently available and show that, although expensive, augmentation therapy has a cost-effectiveness ratio that is similar to many currently used treatments such as hemodialysis etc. To re-examine the cost-effectiveness of intravenous augmentation therapy in the context of recently available data from the NHLBI Registry for Individuals with Severe Deficiency of AAT, we undertook the current cost-effectiveness analysis of augmentation therapy (1, 3, 4). In contrast to prior analyses, the current study incorporates several distinctive features: (1) we model disease progression on the basis of data from the NHLBI Registry, (2) we consider the impact of discounting over time, the impact of quality of life, and the incremental cost of augmentation therapy compared with other pulmonary medications that patients with chronic obstructive pulmonary disease (COPD) commonly use, (3) we consider the costs and benefits of augmentation therapy (on the basis of NHLBI Registry data) over the lifetime of patients, and (4) we perform careful sensitivity analyses to examine the model under extreme conditions. Some of the results of this study have been previously reported in the form of an abstract (5).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Decision Model
A Markov-based decision analytic model was developed to evaluate the cost-effectiveness of different strategies of treating AAT-deficient individuals with intravenous pooled human plasma antiprotease (augmentation therapy). The following strategies were assessed: (1) NO_TREAT = not treating AAT deficiency with augmentation therapy, (2) TREAT_LIFE = treating AAT-deficient individuals who have indications for augmentation therapy for life, and (3) TREAT_LT35 = treating AAT-deficient individuals with augmentation therapy until FEV1 is below 35% predicted (Figure 1) . For each strategy, patients were followed until death in a Markov model consisting of five health states based on the ATS staging system (6): FEV1 50 to 79% predicted, FEV1 35 to 49% predicted, FEV1 below 35% predicted, lung transplantation, and death (Figures 1 and 2) .



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  		Figure 1. Markov model depicting possible annual transitions of patients to different health states.

 


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  		Figure 2. Decision tree depicting the competing treatment strategies and potential annual transitions. 1: Although not shown in this figure, the decision tree structure is identical for all three treatment strategies (TREAT_LIFE, NO_TREAT, and TREAT_LT35).

 
A hypothetical cohort of 30,000 identical patients was evaluated for each strategy using Monte Carlo simulation. In keeping with the mean baseline characteristics of NHLBI Registry participants, the hypothetical population was 46 years old, 50% male, and had an FEV1 of 49% predicted. In the decision model, patients entered a Markov process with yearly cycles, during which they could remain in their current state or transition to another. The analysis took the health care system perspective and considered direct medical costs. All costs were adjusted to 2001 U.S. dollars using the medical services component of the consumer price index. Effectiveness was measured in quality-adjusted life-years (QALYs). An annual discount rate of 3% was applied to costs and effectiveness (7, 8). The model generated mean cost and effectiveness. Strategies were compared using incremental cost-effectiveness ratios (ICERs). A complete glossary of terminology used in pharmacoeconomics, and outcomes research may be reviewed in the International Society for Pharmacoeconomics and Outcomes Research lexicon (9).

Natural History Data
Estimates of the progression of lung dysfunction and mortality rates were obtained from the NHLBI Registry (1). Subjects progressed through the states of lung function on the basis of the mean annual FEV1 decline for patients in the Registry. Each year, the FEV1 decline for a patient was determined by sampling from the distribution of FEV1 decline for the patient's current state of disease (Table 1) . Annual transitional probabilities to death were calculated on the basis of 5-year mortality rates derived from the Registry study. The annual probability of death for patients with FEV1 below 50% was based on augmentation therapy status (i.e., receiving vs. not receiving). Disease-specific mortality rates (i.e., mortality attributed to AAT deficiency) were determined by adjusting all-cause mortality rates from the Registry by standard life table mortality rates. Deaths from causes other than AAT deficiency were also included in the model using standard life table mortality rates. The AAT deficiency–specific mortality rate was added to the mortality rate from other causes to calculate the total annual mortality rate. In the Registry, no significant difference in mortality rates between those receiving and not receiving augmentation therapy was observed for subjects with FEV1 greater than 50%. Therefore, these patients were assigned the same annual probability of death. In the base case analysis, we estimated that 19% of patients with an FEV1 below 15% predicted receive lung transplantation.


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  		TABLE 1. Summary of important natural history variables

 
Cost Data
The base case analysis assumed a 70-kg individual who receives weekly 1-hour augmentation therapy infusions of 60 mg/kg. The costs of augmentation therapy with Prolastin (Bayer) were estimated using the 2001 average wholesale price and Medicare reimbursement rates for a 1-hour infusion (Table 2) (10). Specifically, augmentation therapy costs were based on the actual wholesale price plus Medicare reimbursement rates for weekly 1-hour infusions of 4,200 mg of Prolastin. Although the cost estimate was made using 4,200 mg as an infused dose, the packaging of the drug in 500-mg vials as the smallest dispensing unit required weekly use of 4,500 mg.


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  		TABLE 2. Summary of important cost and quality of life variables

 
The cost of managing patients with AAT deficiency other than augmentation therapy was estimated with data from a retrospective analysis of the cost of managing COPD (11). This retrospective study estimated the cost of healthcare for patients stratified by the same American Thoracic Society COPD staging system that was used to define health states in the current model (6). This study accounted for the cost of medications, oxygen therapy, laboratory and diagnostic tests, clinic and emergency department visits, and hospitalizations. Also, the cost of transplantation and post-transplantation care were based on previously published pharmacoeconomic studies of lung transplant patients (12, 13). All costs were adjusted to 2001 U.S. dollars using the medical care services component of the consumer price index.

Quality of Life Data
This model covers a wide range of disease states that would be expected to differ widely in terms of quality of life. Therefore, it is necessary to explicitly incorporate quality of life into the outcome measure. The recommended measure is the QALY (14). The QALY is a health outcome measure that incorporates both morbidity and mortality on the basis of including preferences or valuation. Each health condition is assigned a quality weight called a utility. Utilities range from 0 (for health states equivalent to death) to 1 (for perfect health). Time spent in a particular state of health is adjusted for quality of life by multiplying the utility by the amount of time spent in that state of health. The resulting measure, QALYs, therefore measure both quantity and quality of time. For example, 1 year spent in a health state with a utility of 0.5 yields 0.5 QALYs (1 x 0.5 = 0.5). The effectiveness of each treatment strategy in this model was calculated by summing all QALYs for patients accumulated during their lifetime (Table 2). Estimates of utility weights were obtained through a prospective survey of pulmonologists experienced in treating AAT deficiency using the health utilities index (Mark III) (15). For each health state in the model, the 14 respondents completed the health utilities index to provide the estimated utility weights.

Incremental Cost-effectiveness Calculation
Competing treatment strategies were compared on the basis of their ICERs. Incremental cost-effectiveness is a measure of the additional cost of one strategy versus another compared with the additional effectiveness it delivers (7, 8). In this calculation, the mean cost and effectiveness are calculated for each strategy. The ICER is calculated by dividing the incremental (additional) mean cost of a more costly strategy by the incremental mean effectiveness of that treatment strategy.

Model Assumptions
The model incorporated the following assumptions: (1) all patients start at age 46 with an FEV1 of 49% predicted (1), (2) augmentation therapy is started immediately when patients enter the model, (3) all patients, including those who do not receive augmentation therapy, receive standard medical care for COPD (16), (4) lung transplantation is considered only when the FEV1 is below 15% predicted, (5) the annual probability of death for lung transplant recipients is the same as for those with FEV1 less than 50% predicted.

Sensitivity Analysis
Sensitivity analyses were conducted to test the robustness of the baseline results to the assumptions and estimates in our model. The exact sensitivity ranges used for these analyses are presented in Tables 1 and 2. One-way sensitivity analysis was conducted for all variables in the model. Sensitivity ranges for annual FEV1 decline and probability of death were determined by 95% confidence intervals. Costs and utility weights were both halved and doubled. The annual discount rate was varied from 0 to 7%. The annual probability of receiving a lung transplant if the FEV1 declines below 15% expected was varied between 5 and 30%. A scenario was run in which patients started the model with an FEV1 of 79% predicted and received augmentation therapy when their FEV1 predicted fell below 65%. To express outcomes in terms of life expectancy, the effect of setting the discount rate to 0% and assigning utility weights equal to 1 for all health states was also analyzed.

Extensive sensitivity analyses were conducted regarding the length of treatment and the duration of clinical benefit of augmentation therapy. The following three scenarios were analyzed independently: (1) treat with augmentation therapy for life, but the benefit begins to diminish after Year 5, and by Year 10, augmentation therapy has no clinical benefit, (2) treat with augmentation therapy for 5 years and then stop, (3) treat with augmentation therapy for 5 years, but clinical benefits last for life.

In addition to one-way sensitivity analysis, we checked the potential impact of a systematic bias of health state utilities by simultaneously halving and doubling all utilities in the same direction. Similar analyses were conducted by changing all costs simultaneously. Finally, a threshold analysis was conducted to determine the annual cost of augmentation therapy at which the ICER of augmentation went below $100,000 and $50,000 per QALY, respectively. For all sensitivity analyses, a variable was considered potentially influential and was analyzed in further detail if it could push the ICER below $100,000 per QALY gained.

DATA version 3.5 by TreeAge Software, Inc. (Williamstown, MA) was used for all analyses.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline Results
Table 3 presents the baseline results of the incremental cost-effectiveness analysis. Treating patients with augmentation therapy for life (TREAT_LIFE) led to the most QALYs (i.e., 7.19) and the highest cost (i.e., $895,243). Treating patients until FEV1 falls below 35% predicted (TREAT_LT35) cost $419,839 and produced 6.64 QALYs. The NO_TREAT strategy cost $92,091 with 4.62 QALYs. The ICER for TREAT_LT35 was $207,841 and for TREAT_LIFE it was $696,933 (Table 3). In comparing directly the TREAT_LIFE with the NO_TREAT strategy, the ICER for TREAT_LIFE was $312,511 per QALY.


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  		TABLE 3. Cost, effectiveness, and incremental cost-effectiveness ratio of treatment strategies

 
Sensitivity Analyses
The ICER exceeded $100,000 per QALY for all treatment strategies in all sensitivity analyses (range: $101,811–$1,073,983). Starting therapy with milder degrees of airflow obstruction (i.e., beginning augmentation therapy when FEV1 < 65% predicted) decreases the cost-effectiveness of augmentation therapy strategies. For the sake of comparison with prior studies, we also considered not discounting cost and not considering quality of life. This was done by setting the discount rate to 0% and setting all utility weights to 1 (calculating the undiscounted cost per life-year saved). This led to a benefit of approximately 9 years of life saved (YLS) at a cost of $1.2 million in the TREAT_LIFE strategy compared with NO_TREAT.

In the scenarios where length of therapy and duration of benefit were varied, treating with augmentation therapy cost $380,000 per additional QALY if the benefit of augmentation therapy diminishes between Years 5 and 10. Treating with augmentation therapy for 5 years and then stopping treatment costs approximately $196,000 per additional QALY. Lastly, treating with augmentation therapy for 5 years with the clinical benefit lasting for life costs $123,000 per additional QALY.

An analysis of the effect of FEV1 transplant threshold on cost-effectiveness showed no significant change in QALYs. Specifically, if transplant occurred at the time of listing (i.e., FEV1 < 30% predicted) the incremental benefit was 0.57 QALYs with an ICER of $628,936.

Even when sensitivity analyses increased and decreased all utilities or costs simultaneously, no strategy produced an ICER below the threshold value of $100,000 per QALY. In threshold analysis, the yearly cost of augmentation therapy needed to be reduced from $54,765 to $14,000 in order for the ICER for TREAT_LIFE to go below $100,000 per QALY gained and to $4,900 for the ICER to go below $50,000 per QALY gained.

Model Validation
We performed a simple validation process to locate any programming errors in the model. Using the mortality data from the Registry, we calculated the 5-year mortality rates for subjects treated and not treated with augmentation therapy. These calculated 5-year mortality rates were virtually identical to the 5-year mortality rates for the patient groups in the model. The calculated 5-year mortality rate was 15% for augmentation therapy recipients and 33% for nonrecipients (55% efficacy). When these groups were analyzed in the Markov model, patients treated with augmentation therapy had a 15.2% 5-year mortality rate, whereas untreated patients had a 33.2% 5-year mortality rate (54% efficacy).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main finding of this study is that the ICER of intravenous augmentation therapy for individuals with severe deficiency of AAT exceeds prior estimates. Specifically, the ICER for lifetime treatment is $312,511 per QALY gained compared with no treatment and $696,933 compared with a shortened course of therapy. These results were robust in extensive sensitivity analyses, and the cost per QALY gained for lifetime augmentation therapy exceeded $100,000 in every analysis. A strategy in which augmentation therapy is limited to patients whose FEV1 is between 35 and 50% of predicted produces an ICER of $207,841 per QALY compared with no augmentation therapy. In the scenario in which augmentation therapy continues for life, the yearly cost of augmentation therapy would need to be reduced from over $50,000 to $4,900 to reach an ICER below $50,000 per QALY gained.

Our estimates of cost per QALY gained for augmentation therapy suggest that augmentation therapy is not as cost-effective as those reported in two earlier analyses (3, 4). Specifically, in the first reported analysis of the cost-effectiveness of augmentation therapy, Hay and Robin (3) reported a cost between $28,000 (in 2001 U.S. dollars, $48,000) and $72,000 (in 2001 U.S. dollars, $124,000) per YLS when augmentation therapy was assumed to have 70% efficacy. When augmentation therapy was assumed to have 30% efficacy, the cost ranged between $50,000 (in 2001 U.S. dollars, $86,000) and $128,000 (in 2001 U.S. dollars, $220,160) per YLS. As the first available cost-effectiveness study of augmentation therapy, this analysis preceded the availability of data regarding the efficacy of augmentation therapy from large observational studies. The study also assumed a lower cost than is currently available, did not account for differences in costs and quality of life between health states, and ascribed a great benefit of augmentation therapy to active smokers.

In the second available cost-effectiveness analysis of augmentation therapy, Alkins and O'Malley (4) estimated the incremental cost to be $13,971 per YLS on the basis of 55% efficacy (in 2001 U.S. dollars, $16,000) and a fixed annual cost of $52,000 for augmentation therapy. Although their cost calculations used efficacy data from the NHLBI Registry, they assumed that augmentation therapy would be used for 5 years but that these costs would be distributed over the entire expected benefit interval of 18 years. As in the previous analysis by Hay and Robin (3), differences in quality of life between health states were not considered. Also, the cost analysis neither considered therapies for COPD other than augmentation therapy nor consistently used a standard discount rate.

Our study analyzed QALYs as opposed to YLS (used in the earlier cost-effectiveness analyses [3, 4]). Assessment of QALYs is the current standard in cost-effectiveness analysis (7). The inclusion of QALYs in our analysis is particularly germane because most patients presented in the Alpha-1 Foundation Research Network and the NHLBI Registries had severe abnormalities of pulmonary function and were symptomatic. For example, in the NHLBI Registry, 72.3% of participants were symptomatic, of whom 83% reported dyspnea on exertion; in the Alpha-1 Foundation Research Network Registry, 35.4% of subjects were prescribed to receive supplemental oxygen. We reasoned that QALYs would be preferable to YLS as a measure of cost-effectiveness in AAT deficiency because QALYs more fully captures the impact of AAT deficiency–related illness. For example, an extension of life with augmentation therapy that came at the cost of severe disability would be captured by measuring QALYs but not by YLS. However, the YLS measure was used in sensitivity analysis when the undiscounted cost per YLS was calculated.

Notwithstanding the attention given to sensitivity analysis in the current study, the decision analysis necessarily assumes several conditions regarding AAT-deficient subjects. Specifically, we assumed that all subjects have the PI*ZZ phenotype, are current nonsmokers, and that the rate of lung function decline is the same in men and women. On the basis of the average characteristics of NHLBI Registry participants, we assumed that patients entering the model were 46 years old and had an FEV1 of 49% predicted. Also, our analysis assumes that all subjects receive usual COPD therapy irrespective of augmentation therapy use.

This analysis adopted the health care system perspective, considering only direct costs. Therefore, the impact of augmentation therapy on indirect costs, such as loss of productivity or leisure time was not formally assessed. We used generous ranges for cost in our sensitivity analysis, with little impact found on the cost-effectiveness of the treatment strategies. Therefore, to the extent that indirect costs do not exceed these bounds, results from our analysis apply.

Our analysis assumes lung transplant was only performed in patients with an FEV1 below 15%. Also, our analysis assumes that 19% of eligible subjects per year undergo lung transplantation. Although this rate is higher than those reported in several available prevalence studies (i.e., 7.1% in the Alpha-1 Foundation Registry [17], 10% in the NHLBI Registry [1], 13% in the St. Louis International Registry [18], and 7.3 to 16.4% in the Scientific Registry of Transplant Recipients [19]), we are unaware of incidence data regarding transplantation for AAT deficiency to guide this estimate. Importantly, sensitivity analysis in which the annual transplant rate was varied from 5 to 30% exerted no significant effect on the ICER of augmentation therapy.

Recommendations about using augmentation therapy should be based foremost on evidence of clinical efficacy and, ideally, also on favorable cost-effectiveness. Furthermore, cost-effectiveness considerations often relate to how the intervention compares with the cost-effectiveness of widely accepted and used interventions, e.g., routine mammography, hypertension screening, and treatment. Comparison of our findings with the cost per QALYs of many current healthcare interventions shows that augmentation therapy confers a high cost per QALY (Table 4) . Indeed, to the extent that our analysis offers more accurate estimates of the cost-effectiveness of augmentation therapy than have heretofore been available, our results call attention to the less favorably high cost-effectiveness ratio of augmentation therapy and, at a minimum, advance enthusiasm for alternate therapies that both have clinical efficacy and are also more cost-effective. We are aware that other approaches to augmentation therapy, whether by alternate routes of administration (e.g., inhalation) or with preparations other than pooled human plasma (e.g., recombinant-produced AAT), are currently being evaluated and may offer more cost-effective options.


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  		TABLE 4. Cost-effectiveness estimates for common health interventions in selected series

 
At the same time, as recently articulated by Wood in his editorial comments regarding whether combined aspirin–clopidogrel therapy should be considered "unattractive" because of a cost-effectiveness ratio exceeding $100,000 (20), we recognize that specific advantages of new, effective therapies may justify "their implementation at higher cost" (21). Indeed, cost-effectiveness is a component of decision-making, not the sole basis. In the specific case of intravenous augmentation therapy with pooled human plasma AAT, this remains the only specific therapy that is currently available for individuals with severe AAT deficiency. Accordingly, the unfavorable cost-effectiveness estimate should be considered in this context. Perhaps more importantly, our findings should encourage the development of future alternative treatments that are both more clinically effective and more cost-effective than existing specific therapy.

Received in original form September 11, 2002; accepted in final form February 3, 2003


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Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313.
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American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency
Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 818 - 900.
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