1 Office for Research and Innovative Projects on Alcohol, Other Addictions and Mental Health, Departments of Psychiatry and Addiction, University of Trieste, Trieste, Italy, 2 Merck Santé, Lyon, France, 3 Jellinek Klinikum, 1001 AS Amsterdam, Netherlands and 4 CORE Center for Outcomes Research, BASEL, Switzerland
* Author to whom correspondence should be addressed at: Office for Research and Innovative Projects on Alcohol, Other Addictions and Mental Health, Departments of Psychiatry and Addiction, University of Trieste, Via De Pastrovich 5/A, 34126 TRIESTE, Italy. Tel.: +39 40 57 10 77; Fax: +39 40 35 00 10; E-mail: polydrug{at}units.it
(Received 31 January 2005; first review notified 21 March 2005; in revised form 27 April 2005; accepted 28 April 2005)
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ABSTRACT |
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INTRODUCTION |
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Alcohol dependence is a common condition associated with high direct and indirect health care costs, principally attributable to the management of secondary comorbidities and lost productivity. Given the prevalence of alcohol-related health problems, the total costs attributable to alcohol use disorders represent a significant proportion of national health care spending. In the US, untreated alcohol-users and drug-users are among the highest cost users of health care (Zook and Moore, 1980). Alcohol-dependent subjects have been reported to consume up to 15 cents for every dollar spent on health care in the US, mostly for the treatment of secondary morbidity (Holder, 1987
). A recent study from France has suggested that costs owing to alcoholism correspond to
1% of the gross national product (Reynaud et al., 2001
), while in Finland, direct health costs alone represent
0.6% of the gross domestic product, while the total health costs may reach 4.3% of the gross domestic product (Hein and Salomaa, 1999
).
Thus, any treatment programme that interrupts the course of chronic alcohol dependence or reduces its severity may result in significant cost savings for society. Alcohol dependence can be treated to some extent with psychosocial intervention programmes or pharmacotherapy with abstinence-promoting drugs or both. However, in spite of the large amount of information available on the economic costs of alcohol dependence, as well as extensive public awareness of this, there is little data on the cost and savings associated with the different detoxification and rehabilitation strategies used in the management of alcohol dependence. In a 14 year survey of health care spending by 3068 alcohol-dependent subjects identified in a North American health insurance claims database (Holder and Blose, 1991, 1992
), total health care expenditure rose with time in a more-or-less linear manner. Costs rose steeply when the alcohol-related problem was identified. From this moment, cost accrual was very different according to whether the individual was successfully treated or not. In untreated patients, costs continued to rise, whereas in treated patients, costs fell to pre-diagnosis values over a 3-year period. Expenditure for 2355% of the patients fell to below pre-treatment values.
Moreover, little data are available comparing the efficiency of individual psychosocial and pharmacological interventions that have been shown to be useful in treating alcohol dependence. A study by Holder et al. (1991) compared the efficiency of 33 different treatment modalities using a semi-quantitative categorical method. This identified large differences between different treatments, with brief interventions being considered the most cost-effective. This analysis was repeated and refined 5 years later (Finney and Monahan, 1996
), and the ranking system was somewhat changed. At this time, clinical trials of pharmacological adjuvant therapy for alcohol dependence were available. However, only oral and implanted disulfiram were assessed with the former being considered not particularly cost-effective. As part of Project MATCH, costs and savings were determined in a prospective manner, and compared between different psychosocial interventions (Holder et al., 2000
). Again, differences in the efficiency of the various treatment options were observed in different patient populations, with motivational enhancement therapy seeming to be the most cost-effective overall.
Currently, the only pharmacological adjuvant therapy for which cost-efficacy studies have been published is acamprosate. No such quantitative data are available on the cost-efficacy of naltrexone or disulfiram. Acamprosate is an abstinence-promoting drug that has been evaluated widely in clinical trials (Mann, 2004) that have provided generally consistent data on the relative treatment benefit in terms of abstinence rates. A recent meta-analysis of these data has estimated the relative risk of remaining abstinent conferred by a 6 month treatment period with acamprosate in recently detoxified subjects to be 1.47 (Mann et al., 2004
). In addition, there is evidence that acamprosate can reduce drinking in those subjects who do not remain abstinent (Chick et al., 2003
).
On the basis of these clinical data, and taking into account the known health care costs associated with alcohol dependence, a number of modelling studies have been performed in order to estimate the efficiency associated with the use of acamprosate in this population. In addition, a further cohort study has measured health care costs and effectiveness directly, comparing subjects taking acamprosate with those without pharmacotherapy. The aim of this review is to provide a critical assessment of these pharmacoeconomic studies in the context of the overall costs of alcohol dependence.
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PHARMACOECONOMIC STUDIES OF ACAMPROSATE |
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The validity of a given Markov model is evidently critically dependent on the accuracy with which the probabilities attributed to each node are known. For this reason, sensitivity analysis is necessary to determine the extent to which the results of the model are affected by varying these input variables. The principal limitations of such modelling techniques are the limited precision of the input probability variables, the arbitrary choice of outcome parameters to include in the model, which may not correspond to real cost drivers in the real world, and the assumption that the different probability values are independent of each other and do not vary with time, which may be difficult to demonstrate. Nevertheless, studies using Markov modelling techniques allow the projection of short-term endpoints (such as abstinence or controlled drinking) to long-term outcomes, such as cirrhosis, hepatic carcinoma, and neurological disease. Such information is often not feasible to obtain in a real prospective study owing to limitations on the duration of the study.
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FIRST GERMAN COST-EFFICACY ANALYSIS |
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This study demonstrated lifetime savings attributable to acamprosate treatment of 1300 (
1450 at 2004 values; lower boundary:
226; upper boundary:
4921) per additional abstinent patient (Fig. 1). These savings were principally owing to reductions in hospitalization and rehabilitation costs. A sensitivity analysis was performed in which values for abstinence rates and duration of hospitalization were varied. Acamprosate use was found to be cost saving in 78% of the scenarios. The principal determinant of efficiency was found to be the differential rate of abstinence. The savings generated also varied according to the unitary hospital costs. The study thus demonstrated that acamprosate use led to a better clinical outcome at reduced cost, and was thus dominant with respect to standard care in terms of cost-efficacy.
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SECOND GERMAN COST-EFFICACY ANALYSIS |
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This multi-parametric model predicted a lower incidence of acute alcoholic psychosis, hepatic disease, gastrointestinal pathologies, cardiomyopathy, suicide, and accidental death in alcohol-dependent patients treated with acamprosate. This would translate into decreased mortality, with life expectancy in the standard care population being 14.7 years and in the acamprosate cohort being 15.9 years. Discounted at 5% per annum, this corresponded to a life-year gain of 0.52 years attributable to acamprosate.
The lifetime direct medical costs in the acamprosate and standard care groups were calculated using standard 1996 German health care costs for hospitalization, outpatient care, and drug acquisition. In terms of costs, lifetime savings in direct medical costs (discounted at 5% per annum) of 881 (
983 at 2004 values) per patient were predicted in the acamprosate-treated population (Fig. 2). Confidence intervals or other measures of precision were not provided. This figure is rather lower than that put forward by Schädlich and Brecht (see above); this difference could be attributed to the use of a different algorithm and different assumptions in the Markov model, notably the attribution of health costs to the patients who remained abstinent. Nonetheless, this modelling study also demonstrated that the use of acamprosate resulted in significant net lifetime health care cost savings, in spite of the acquisition costs of the drug itself.
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The principal strength of this model lies in the extensive range of health parameters modelled. In addition, the likelihood that successfully treated subjects would continue to accrue alcohol-related health care costs was taken into account. Economic data and clinical data were obtained from compatible sources. Once again, the weakness of the model is that long-term predictions on costs and medical benefits are made in the absence of any clinical data on the outcome of acamprosate-treated subjects beyond 2 years of treatment. However, the assumption of a sustained benefit is widely accepted and the impact of this assumption was explicitly addressed in the sensitivity analysis that showed acamprosate treatment to be cost-saving even in the absence of a difference in relapse rate beyond 2 years. Moreover, there is no evidence for any rebound effect of acamprosate on drinking following treatment discontinuation.
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BELGIAN COST-BENEFIT ANALYSIS |
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The Markov model principally evaluated outcomes related to drinking relapse, and the health care costs associated with treating this. These outcomes were outpatient follow-up, institutional follow-up, outpatient detoxification, inpatient detoxification, loss to follow-up, and death. Each of these outcome states were allocated fixed physician consultation costs, hospitalization costs (acute and long-term), drug costs, and laboratory examination costs. These were based on standard Belgian health care costs in 1997. The only secondary alcoholic comorbidity included in the model was liver disease (cirrhosis, but not liver cancer), as this was the only one the evolution of which was expected to vary as a function of abstinence outcome over the 2 year time-frame of the study. A fixed cost for management of liver disease (11 977 per year; 2004 values) was allocated to 1% of relapsing patients at each stage of the model, no cost being allocated to abstinent patients.
The direct medical costs per patient over 2 years were calculated to be 5255 (
5796 at 2004 values) for the acamprosate treated cohort, and
5783 (
6379 at 2004 values) for the standard care cohort. The cost savings attributable to acamprosate use were thus
582 per patient over the 2 year period. Once again, the principal cost reductions were those imputable to hospitalization or rehabilitation (Fig. 3). No precision estimates were provided. The authors calculated that extrapolating this data to all alcohol-dependent patients entering detoxification programmes in Belgium could result in overall annual savings to the national health service of
1.741.86 million (
1.922.05 million at 2004 values).
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This model presents an advantage over the two previous studies in that it only assessed health care costs over a 2 year period, rather than lifetime. The probabilities assigned to the nodes of the Markov model can thus be estimated with confidence, and no assumptions are made about long-term outcome for which no clinical data are available. On the other hand, the cost data are derived from the Belgian health care system, whereas the clinical data come from an Austrian study in which abstinence rates were somewhat lower than those observed elsewhere.
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SPANISH COST-BENEFIT ANALYSIS |
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In the first step, the overall lifetime cost of treatment of all alcohol-dependent patients in Spain was determined, using a discount rate of 5% per annum. From this, an annual cost of alcohol dependence of 1657 million (
1975 million at 2004 values) to the Spanish economy was calculated, corresponding to
2640 per patient per year (
3147 at 2004 values). Of the total costs, 25.7% corresponded to direct costs and 74.3% to indirect costs.
In the second step, the lifetime cost saving generated by the successful rehabilitation of an individual patient with no pathological sequelae was estimated to be 23 528 (
28 046 at 2004 values). In the final step, the net cost savings attributable to acamprosate could be determined in each of these scenarios, by incorporating in the model the drug acquisition costs of acamprosate, and a differential abstinence rate calculated from the basket of clinical trials of 29.1% for acamprosate-treated patients and 22.0% for untreated patients. The impact of treatment programmes could then be ascertained in a variety of scenarios, relating to the prevalence of alcohol dependence, the proportion of patients achieving stable abstinence, and the proportion of rehabilitated patients free of post-detoxification comorbidity. Net cost savings were identified for acamprosate treatment regardless of the scenarios envisaged. In the base-case scenario (50% of patients treated, differential abstinence rate of 29.1%, and 50% of patients with no long-term consequences) total potential cost savings were estimated as
210 million (2004 values). These savings carried from
39 million (2004 values) in the most conservative scenario (40% of patients treated, differential abstinence rate of 10%, and 25% of patients with no long-term consequences) to
261 million (2004 values) in the most optimistic scenario (60% of patients treated, differential abstinence rate of 29.1%, and 75% of patients with no long-term consequences).
Again the strength of this model lies in the range of variables and outcomes assessed, and indeed this is the only study to have estimated indirect costs and savings. The clinical data were obtained from a basket of clinical trials performed in different countries, which, on the one hand, more closely approach average treatment outcomes compared with single studies in which observed abstinence rates may be dependent on individual study protocols. On the other hand, the assumptions that these pooled abstinence rates are applicable to treatment programmes for alcohol dependence in Spain cannot be tested. However, a subsequent clinical trial performed in Spain (Gual and Lehert, 2001) provided an estimate of the differential abstinence rate of 35%, somewhat higher than that used in the modelling study. Indeed, inspection of abstinence rates between studies performed in different countries shows the treatment benefit attributable to acamprosate to be quite similar from one study to the other (Mann, 2004
). The relative benefit in terms of continuous abstinence associated with 6 months of treatment with acamprosate estimated in the meta-analysis of 16 clinical trials was 1.47. Another strength of the study lies in the modelling of the outcome at two different time-horizons. However, the projection of long-term outcome from the clinical trial data remains problematic, as in the German study.
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PROSPECTIVE GERMAN COST-EFFECTIVENESS ANALYSIS |
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Direct medical costs were significantly lower in the acamprosate cohort than in the standard care cohort by 339 in 2004 (
363). These cost savings were generated mainly by a reduced rate of hospitalization (Fig. 4). Indirect costs, principally lost productivity, were also lower in the acamprosate cohort, although this difference (
99;
106) was not statistically significant. However, direct costs contributed 77% of the total costs measured. The cost-effectiveness of standard care was evaluated at
9790 (
10 493 at 2004 values) per abstinent patient compared with a figure of
4857 (
5206 at 2004 values) per abstinent patient for acamprosate treatment, a 2-fold difference. Precision estimates were not provided.
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STRENGTHS AND WEAKNESSES |
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DIRECTIONS FOR FUTURE RESEARCH |
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The currently available pharmacoeconomic data have been obtained from studies built on the hypothesis that the effect of acamprosate is to increase the probability of achieving abstinence. However, in everyday practice, potential outcomes encompass not only abstinence and relapse, but also a reduction in drinking compared with pre-treatment levels. Since the direct medical costs of alcohol dependence are closely associated with the severity of dependence (McKenna et al., 1996), such an outcome would be expected to result in cost savings. Acamprosate has indeed been demonstrated to reduce alcohol consumption in subjects included in the acamprosate clinical trial programme (Chick et al., 2003
). This point is particularly important in order to evaluate acamprosate treatment strategies where the drug is used without a prior formal detoxification, such as was used in the North American clinical trial of acamprosate (Mason, 2001
).
The long-term economic impact of acamprosate treatment has been modelled assuming that abstinence rates observed at the end of the observation periods of clinical trials (2 years) are sustained, and this assumption merits validation. Because acamprosate has now been available in certain countries for over 10 years, it should be possible to address this issue through analysis of long-term outcome recorded in patient registries.
Little information is available on the impact of acamprosate on the indirect costs of alcohol dependence. Since these outweigh direct costs, this impact may be significant. A recent observational study (Kiritzé-Topor et al., 2004) has demonstrated that acamprosate reduces the social consequences of alcohol dependence as measured with the Alcohol-Related Problems Questionnaire (Chick et al., 1991
; Patience et al., 1997
). This scale quantifies a number of non-medical consequences of alcohol dependence, such as legal, professional, or family problems. Such an approach may be suitable for quantifying the impact of acamprosate on the indirect costs of alcohol dependence.
It would also be useful to compare the cost-efficiency of treatment using acamprosate with that of other pharmacological adjuvant treatments used in the rehabilitation of alcohol-dependent patients, such as naltrexone or disulfiram, for neither of which any pharmacoeconomic data has been published. The ongoing COMBINE study in the US (The COMBINE Study Research Group, 2003) that compares treatment with acamprosate, naltrexone, or both combined with different levels of psychosocial intervention, may provide the necessary outcome data to perform a comparative modelling study of the cost-effectiveness of naltrexone and acamprosate.
Finally, the data on acamprosate could usefully be completed with cost-utility studies in which adjustments are made for changes in the quality of life. Since other studies have indeed demonstrated that acamprosate treatment improves the poor quality of life observed in alcohol-dependent patients (Morgan et al., 2004), pharmacoeconomic studies addressing cost-utility would be expected to reinforce the economic argument for using acamprosate.
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CONCLUSIONS |
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