IMIB, Institute for Medical Informatics and Biostatistics, Riehen, Switzerland,
1 MerkLipha S.A., Lyon, France and
2 Department of Gastroenterology, Kent and Sussex Hospital, Tunbridge Wells, UK
Received 13 January 2000; in revised form 6 April 2000; accepted 19 April 2000
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ABSTRACT |
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INTRODUCTION |
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In the absence of the toxic effects of alcohol in patients who remain abstinent, complications of alcoholism either will not occur in patients who do not have the complication, may be reversible, or have an improved survival outcome. A number of substances, including acamprosate, have been shown to reduce short- to medium-term relapse rates in detoxified alcohol-dependent patients (Pelc et al., 1994; Paille et al., 1995a
,b
; Sass et al., 1996a
; Whitworth et al., 1996
; Geerlings et al., 1997
) but the long-term effects on incidence and progression of clinical complications, life expectancy and costs have not been assessed.
In this context, a computer simulation model was developed to estimate the lifetime medical and cost outcomes for a cohort of detoxified alcoholic patients following either standard counselling therapy, or standard counselling therapy with adjuvant acamprosate in the German setting (Sass et al., 1996a). The hypothesis tested was that adjuvant acamprosate therapy would decrease the incidence and progression of long-term complications of alcoholism, leading to an increase in life expectancy, with the costs of acamprosate therapy being offset by a reduction in costs due to complications avoided.
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METHODS |
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Both undiscounted and discounted costs and life years gained were calculated using a real discount rate of 5% per annum.
One-way sensitivity analysis on life expectancy and total lifetime costs for patients treated with adjuvant acamprosate was performed in order to identify factors exerting a major influence on these outcomes. Each probability and cost parameter was varied one at a time by ±10%, while holding all other parameters constant. Break-even analysis was performed on the costs of 48 weeks adjuvant acamprosate therapy. The acquisition costs of acamprosate were varied until the total lifetime costs (costs of therapy + costs of treating events) were equal to the total costs for standard therapy alone.
The full model structure was built up from a series of Markov submodels that simulate the progression of the important complications of alcoholism. The submodels were run in parallel, allowing the cohort to develop more than one complication concurrently, as has previously been applied in diabetes mellitus, another disease with multiple long-term complications (Palmer et al., 1996, 1999
, 2000
). Overall mortality was calculated by integrating complication-specific mortality calculated within each submodel with non-complication-specific mortality (Fig. 2
) (Welch et al., 1996
; Anonymous, 1996d
). The model was programmed using TOM (Tools for Outcomes Modelling)TM software from IMIB (Basel/Riehen, Switzerland).
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RESULTS |
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DISCUSSION |
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Alcohol-dependent patients have increased morbidity and mortality in comparison to the general population (Gillis, 1969; Pell and D'Alonzo, 1973
; Lesch et al., 1986
; Piette et al., 1998
). Abstinent patients retain considerable excess morbidity and mortality compared to the general population (Pell and D'Alonzo, 1973
). Life expectancies calculated by the model for a male cohort of weaned alcohol-dependent patients were 55.7 and 56.9 years for standard therapy alone or adjuvant acamprosate therapy respectively. These results are similar to the results of an observational study in Austria that demonstrated total life expectancy of 50 years in previously hospitalized chronic alcoholic patients, compared to a control group with life expectancy of 73.9 years (Lesch et al., 1986
). Other studies have also demonstrated that treatment of alcoholism/ abstinence maintenance may improve survival, and be cost-saving (Holder and Blose, 1992
; Schadlich and Brecht, 1998
). The improvements in life expectancy seen with adjuvant acamprosate therapy are substantial, even under conservative assumptions, when compared to other interventions commonly used in modern medicine, such as thrombolytic therapy for myocardial infarction (15 months gained in comparison to no thrombolytic therapy), routine beta-blocker therapy for prophylaxis against recurrent myocardial infarction (1.25.6 months gained) ticlopidine compared to aspirin for patients at high risk of stroke (0.6 months), or interferon therapy in patients with chronic hepatitis B (37 months) (Wright and Weinstein, 1998
).
It was assumed that the suicide rate of abstinent patients returned to the level of the general population. However, due to underlying psychological co-morbidity (Kessel and Grossman, 1961; Driessen et al., 1998
), this may overestimate the reduction in suicide rates seen with abstinence. Due to the uncertainty surrounding the effect of abstinence on suicide, more detailed sensitivity analysis was performed, which revealed that, even when no effect of abstinence on suicide was assumed, acamprosate still led to savings of both lives and costs.
Sensitivity analysis revealed the importance of abstinence rates, liver disease, and suicide in alcoholism therapy. Interventions that improve abstinence rates are likely to have a critical impact on the outcomes of alcoholic patients who have been detoxified.
Limitations
The validity of health economics analyses is limited by the availability of appropriate medical and cost data. The data available from the literature are themselves limited by the aims, populations, and methodology of the clinical trials that generate the data. Prevalence rates of complications were reasonably well reported, but incidence rates of complications including peripheral neuropathy, alcoholic cardiomyopathy in alcohol-dependent patients generally, and in abstinent (recovering) patients specifically have been poorly documented. Every attempt was made to apply probabilities from the German setting, but data from studies performed in other countries were sometimes applied. Although not ideal, in the absence of other information, this solution allows the filling of data gaps until more country-specific information becomes available.
Measures of dispersion of the results were not calculated. For an accurate estimation of confidence intervals, each probability and cost item needs to be defined as a distribution. In reality, it is difficult to find probabilities and costs even as single (point value) numbers, and distributions are rarely reported. Therefore, distributions must be artificially created or assumed, leading to the calculation of artificial confidence intervals that may or may not reflect reality. Thorough sensitivity analysis is the preferred method of quantifying uncertainty (Siegel et al., 1996; Weinstein et al., 1996
).
Quality of life changes were not explicitly assessed in the analysis, although improved quality of life is implicit in a reduction in severity of complications. Quality-adjustment of LYG would allow a cost-utility analysis. In the case where adjuvant acamprosate therapy has lower costs and higher effectiveness (life expectancy), adjustment for quality of life improvements would increase the dominance of adjuvant acamprosate in comparison to standard therapy.
In most of the clinical trials of acamprosate, the primary efficacy assessment until now has been absolute abstinence. Although this endpoint is relatively clear-cut, the effect of acamprosate on reduction in craving and reduced levels of alcohol consumption has not been taken into account, and the improvements in morbidity and mortality due to lower levels of alcohol consumption (Lelbach, 1975; Pequignot et al., 1978
; Becker et al., 1996
; Almela et al., 1997
; Gronbaek et al., 1998
) may have been underestimated in this study.
Not every possible alcohol-related complication was modelled. Other alcohol-related problems, such as skeletal myopathy (Fernandez-Sola et al., 1995) autonomic neuropathies, (Monforte et al., 1995
), other carcinomas (Pell and D'Alonzo, 1973
), alcohol-related dementia and Korsakoff syndrome (Kendell and Staton, 1966
), para-suicide (Chignon et al., 1998
; Driessen et al., 1998
), and non-fatal accidents (Piette et al., 1998
), were not taken into account. Additionally, not every possible alternative alcoholism therapy, such as outpatient long-term intensive therapy for alcoholics (Ehrenreich et al., 1997
) or adjuvant naltrexone therapy (O'Malley et al., 1992
, 1996a
,b
; Volpicelli et al., 1992
, 1995a
, b
, 1997
; Mason et al., 1994
; O'Brien et al., 1996
) was included in this analysis. Brief intervention therapy was also not considered, as this generally applies to a different population of patients identified as problem drinkers (not abstinent alcoholics) with the intention of reducing levels of alcohol consumption to safer levels (Anonymous, 1996b
; Edwards and Rollnick, 1997
; Higgins-Biddle et al., 1997
; McIntosh et al., 1997
; Senft et al., 1997
; Wilk et al., 1997
; Cordoba et al., 1998
; Dyehouse and Sommers, 1998
; Marlatt et al., 1998
; Wright et al., 1998
). While other interventions that improve abstinence maintenance or reduce the level of alcohol consumption are likely to improve clinical outcomes, they too will need to be subject to assessment of their efficiency (i.e. balance of costs versus effectiveness).
The side-effects of adjuvant acamprosate therapy were not considered in the analysis, as acamprosate is generally well-tolerated, and the side-effects that occur are mild, short-lived, reversible, and not significantly different from those occurring in placebo-treated patients (Paille et al., 1995a,b
; Sass et al., 1996a
,b
; Whitworth et al., 1996
; Geerlings et al., 1997
; Pelc et al., 1997
; Poldrugo, 1997
).
Although indirect costs were not included in this analysis, the indirect costs due to alcoholism have previously been estimated at DEM 4422 million in west Germany in 1990, DEM 2284 million from premature mortality, DEM 1150 million from inability to work, and DEM 988 million from premature retirement. This was more than triple the direct costs (DEM 1150 million). If indirect costs had been considered in this analysis, it is possible that the savings from a societal perspective could be considerably greater.
Finally, the abstinence rates for the acamprosate-treated cohort used in this analysis were taken from a single long-term study (Sass et al., 1996a). The results from this study were used in the model because acamprosate was given in addition to counselling and/or psychotherapy, reflecting the real-life management of alcohol abstinence in the German setting. Another long-term study (2 years to 1 year drug therapy plus 1 year no-drug follow-up, 448 patients) in Austria (Whitworth et al., 1996
) also showed significantly superior 2-year abstinence rates, compared to placebo. However, the absolute abstinence rates for both the placebo and acamprosate groups were lower, and the difference between abstinence rates at 2 years for the placebo and acamprosate groups was less than those reported in the German trial. When the abstinence rates taken from the Austrian trial were simulated in the model, adjuvant acamprosate therapy was still life-saving (0.55 LYG discounted at 5% p.a.), and cost neutral (both groups with total lifetime costs of ~DEM 53 200 per patient, discounted at 5% p.a.). However, a French study showed a significant difference in abstinence rates at 6 months, but not at 12 or 18 months, although a positive trend in favour of acamprosate was seen (Paille et al., 1995a
,b
). A formal meta-analysis could provide more definitive estimates of the long-term effectiveness of acamprosate, although combining results from studies with heterogeneous patient populations, drug doses, severity of illness, and differences in psychological support/counselling and other concomitant therapy would be difficult.
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CONCLUSIONS |
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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REFERENCES |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Almela, P., Aparisi, L., Grau, F., Sempere, J. and Rodrigo, J. M. (1997) Influence of alcohol consumption on the initial development of chronic pancreatitis. Revista Espanola De Enfermedades Digestivas 89, 741752.[Medline]
Anonymous (1989) Sozioökonomie der chronischen Herzinsuffizienz. HealthEcon AG, Basel.
Anonymous (1996a) Diagnosedaten der Krankenhauspatienten. Metzler-Poesche, Stuttgart.
Anonymous (1996b) A cross-national trial of brief interventions with heavy drinkers. WHO Brief Intervention Study Group. American Journal of Public Health 86, 948955.[Abstract]
Anonymous (1996c) Rote Liste. Arzneimittelverzeichnis des Bundesverbandes der Pharmazeutischen Industrie e.V. (BPI). Rote Liste GmbH, Frankfurt/Main.
Anonymous (1996d) Todesursachenstatistik. Statistiches Bundesamt, Wiesbaden.
Anonymous (1998a) Kostennachweis der Krankenhäuse 1996.
Anonymous (1998b) Krankheitsartenstatistik 1996: Arbeitsunfähigkeit und Krankenhausfälle nach Krankheitsarten, Alter und Dauer. AOK-Bundesverband, Bonn.
Anonymous (1998c) Pschyrembel. Walter de Gruyter, Berlin.
Banz, K., Rohrbacher, R. and Schwicker, D. (1993) Die sozioökonomie der chronischen Lebererkrankungen in Deutschland. HealthEcon AG, Basel.
Baudet, M., Rigaud, M., Rocha, P., Bardet, J. and Bourdarias, J. P. (1979) Reversibility of alcoholic cardiomyopathy with abstention from alcohol. Cardiology 64, 317324.[ISI][Medline]
Becker, U., Deis, A., Sorensen, T. I., Gronbaek, M., Borch-Johnsen, K., Muller, C. F., Schnohr, P. and Jensen, G. (1996) Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology 23, 10251029.[ISI][Medline]
Berglund, M. and Ojehagen, A. (1998) The influence of alcohol drinking and alcohol use disorders on psychiatric disorders and suicidal behavior. Alcoholism: Clinical and Experimental Research 22 (Suppl.), 333S345S.[ISI][Medline]
Berlakovich, G. A., Steininger, R., Herbst, F., Barlan, M., Mittlbock, M. and Muhlbacher, F. (1994) Efficacy of liver transplantation for alcoholic cirrhosis with respect to recidivism and compliance. Transplantation 58, 560565.[ISI][Medline]
Brecht, J. G., Poldrugo, F. and Schadlich, P. K. (1996) Alcoholism the cost of illness in the Federal Republic of Germany. Pharmacoeconomics 10, 484493.[ISI][Medline]
Bundesamt für Sozialversicherung [Federal Office of Social Insurance] (1998) Handbuch zur Standardisierung der medizinischen und wirtschaftlichen Bewertung medizinischer Leistungen. [Manual for the standardisation of clinical and economic evaluation of medical technology]. Swiss Federal Office of Social Security, Bern.
Cales, P., Desmorat, H., Vinel, J. P., Caucanas, J. P., Ravaud, A., Gerin, P., Brouet, P. and Pascal, J. P. (1990) Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding. Gut 31, 12981302.[Abstract]
Chignon, J. M., Cortes, M. J., Martin, P. and Chabannes, J. P. (1998) Attempted suicide and alcohol dependence: results of an epidemological survey. Encephale 24, 347354.[ISI][Medline]
Cordoba, R., Delgado, M. T., Pico, V., Altisent, R., Fores, D., Monreal, A., Frisas, O. and Lopez, D. V. (1998) Effectiveness of brief intervention on non-dependent alcohol drinkers (EBIAL): a Spanish multi-centre study. Family Practice 15, 562568.
Demakis, J. G., Proskey, A., Rahimtoola, S. H., Jamil, M., Sutton, G. C., Rosen, K. M., Gunnar, R. M. and Tobin, J. R. (1974) The natural course of alcoholic cardiomyopathy. Annals of Internal Medicine 80, 293297.[ISI][Medline]
Driessen, M., Veltrup, C., Weber, J., John, U., Wetterling, T. and Dilling, H. (1998) Psychiatric co-morbidity, suicidal behavior and suicidal ideation in alcoholics seeking treatment. Addiction 93, 889894.[ISI][Medline]
Dyehouse, J. M. and Sommers, M. S. (1998) Brief intervention after alcohol-related injuries. Nursing Clinics of North America 33, 93104.[ISI][Medline]
Edwards, A. G. and Rollnick, S. (1997) Outcome studies of brief alcohol intervention in general practice: the problem of lost subjects. Addiction 92, 16991704.[ISI][Medline]
Ehrenreich, H., Mangholz, A., Schmitt, M., Lieder, P., Volkel, W., Ruther, E. and Poser, W. (1997) Olita: an alternative in the treatment of therapy-resistant chronic alcoholics. First evaluation of a new approach. European Archives of Psychiatry and Clinical Neuroscience 247, 5154.[ISI][Medline]
Fernandez-Sola, J., Sacanella, E., Estruch, R., Nicolas, J., Grau, J. M. and Urbano-Marquez, A. (1995) Significance of type II fiber atrophy in chronic alcoholic myopathy. Journal of the Neurological Sciences 130, 6976.[ISI][Medline]
Frank, B. and Zoller, W. G. (1994) [Transjugular intrahepatic portosystemic stent shunt (TIPS). 2nd Freiburg Symposium. Freiburg Medical University Clinic 11/12 March 1994] Transjugularer intrahepatischer portosystemischer Stent-Shunt (TIPS). 2. Freiburger Symposium. Medizinische Universitatsklinik Freiburg, 11./12. 3. 94. Bildgebung 61, 136138.[Medline]
Geerlings, P., Ansoms, C. and van den Brink, W. (1997) Acamprosate and prevention of relapse in alcoholics. European Addiction Research 3, 129137.[ISI]
Gerbes, A. L. (1997) [Experimental methods in hepatology. Guidelines of the German Work Group for Study of the Liver. Therapy of ascites in liver diseases. German Work Group for Study of the Liver] Experimentelle Methoden in der Hepatologie. Richtlinien der Deutschen Arbeitsgemeinschaft zum Studium der Leber (GASL). Aszitestherapie bei Lebererkrankungen. Zeitschrift für Gastroenterologie 35, 295300.[ISI][Medline]
Gerhardt, T. C., Goldstein, R. M., Urschel, H. C., Tripp, L. E., Levy, M. F., Husberg, B. S., Jennings, L. W., Gonwa, T. A. and Klintmalm, G. B. (1996) Alcohol use following liver transplantation for alcoholic cirrhosis. Transplantation 62, 10601063.[ISI][Medline]
Gillis, L. S. (1969) The mortality rate and causes of death of treated chronic alcoholics. South African Medical Journal 43, 230232.[Medline]
Grant, B. F., Dufour, M. C. and Harford, T. C. (1988) Epidemiology of alcoholic liver disease. Seminars in Liver Disease 8, 1225.[ISI][Medline]
Greiner, W. (1999) Oekonomische Evaluationen von Gesundheitsleistungen. Fragestellungen, Methoden and Grenzen dargestellt am Beispiel der Transplantationsmedizin, 1st edn. Nomos Verlagsgesellschaft, Baden-Baden.
Gronbaek, M., Becker, U., Johansen, D., Tonnesen, H., Jensen, G. and Sorensen, T. I. (1998) Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. British Medical Journal 317, 844848.
Henderson, J. M. (1992) Effect of alcohol consumption on variceal rebleeding and mortality. HPB Surgery 6, 137139.[Medline]
Higgins-Biddle, J. C., Babor, T. F., Mullahy, J., Daniels, J. and McRee, B. (1997) Alcohol screening and brief intervention: where research meets practice. Connecticut Medicine 61, 565575.[Medline]
Holder, H. D. and Blose, J. O. (1992) The reduction of health care costs associated with alcoholism treatment: a 14-year longitudinal study. Journal of Studies on Alcohol 53, 293302.[ISI][Medline]
Holder, H., Lennox, R. and Blose, J. (1992) The economic benefits of alcoholism treatment: a summary of twenty years of research. Journal of Employee Assistance Research 1, 6382.
Imperiale, T. F. and McCullough, A. J. (1990) Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Annals of Internal Medicine 113, 299307.[ISI][Medline]
Jacob, A. J., McLaren, K. M. and Boon, N. A. (1991) Effects of abstinence on alcoholic heart muscle disease. American Journal of Cardiology 68, 805807.[ISI][Medline]
Kendell, R. E. and Staton, M. C. (1966) The fate of untreated alcoholics. Quarterly Journal of Studies on Alcohol 27, 3041.[ISI][Medline]
Kessel, N. and Grossman, G. (1961) Suicide in alcoholics. Alcohol and Road Accidents 2, 16711672.
Kumar, S., Stauber, R. E., Gavaler, J. S., Basista, M. H., Dindzans, V. J., Schade, R. R., Rabinovitz, M., Tarter, R. E., Gordon, R. and Starzl, T. E. (1990) Orthotopic liver transplantation for alcoholic liver disease. Hepatology 11, 159164.[ISI][Medline]
Lehmann, F. G. and Wegener, T. (1979) Etiology of human liver cancer: controlled prospective study in liver cirrhosis. Journal of Toxicology and Environmental Health 5, 281299.[ISI][Medline]
Lelbach, W. K. (1975) Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Annals of the New York Academy of Sciences 252, 85105.[ISI][Medline]
Lesch, O. M., Lesch, E., Dietzel, M., Mader, R., Musalek, M., Walter, H. and Zeiler, K. (1986) [Chronic alcoholism-alcohol sequelae-causes of death] Chronischer Alkoholismus-Alkoholfolgekrankheiten-Todesursachen. Wiener Medizinische Wochenschrift 136, 505 515.[ISI][Medline]
Maier, K. P. (1991) Hepatitis Hepatitisfolgen, 3rd edn. Georg Thieme, Stuttgart.
Marlatt, G. A., Baer, J. S., Kivlahan, D. R., Dimeff, L. A., Larimer, M. E., Quigley, L. A., Somers, J. M. and Williams, E. (1998) Screening and brief intervention for high-risk college student drinkers: results from a 2-year follow-up assessment. Journal of Consulting and Clinical Psychology 66, 604615.[ISI][Medline]
Mason, B. J., Ritvo, E. C., Morgan, R. O., Salvato, F. R., Goldberg, G., Welch, B. and Mantero-Atienza, E. (1994) A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcoholism, Clinical and Experimental Research 18, 11621167.[ISI][Medline]
Mason, J., Drummond, M. and Torrance, G. (1993) Some guidelines on the use of cost-effectiveness league tables. British Medical Journal 306, 570572.[ISI][Medline]
McCormick, P. A., Morgan, M. Y., Phillips, A., Yin, T. P., McIntyre, N. and Burroughs, A. K. (1992) The effects of alcohol use on rebleeding and mortality in patients with alcoholic cirrhosis following variceal haemorrhage. Journal of Hepatology 14, 99103.[ISI][Medline]
McIntosh, M. C., Leigh, G., Baldwin, N. J. and Marmulak, J. (1997) Reducing alcohol consumption. Comparing three brief methods in family practice. Canadian Family Physician 43, 19591962.[ISI][Medline]
Merletti, F., Boffetta, P., Ciccone, G., Mashberg, A. and Terracini, B. (1989) Role of tobacco and alcoholic beverages in the etiology of cancer of the oral cavity/oropharynx in Torino, Italy. Cancer Research 49, 49194924.[Abstract]
Milani, L., Bagolin, E. and Sanson, A. (1989) Improvement of left ventricular function in chronic alcoholics following abstinence from ethanol. Cardiology 76, 299304.[ISI][Medline]
Moewes, M., Effer, E. and Hess, R. (1998) Kölner Kommentar zum EBM. 2. Auflage edn. Deutscher Ärzte-Verlag, Köln.
Monforte, R., Estruch, R., Valls-Solö, J., Nicolas, J., Villalta, J. and Urbano-Marquez, A. (1995) Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Archives of Neurology 52, 4551.[Abstract]
O'Brien, C. P., Volpicelli, L. A. and Volpicelli, J. R. (1996) Naltrexone in the treatment of alcoholism: a clinical review. Alcohol 13, 3539.[ISI][Medline]
O'Malley, S. S., Jaffe, A. J., Chang, G., Schottenfeld, R. S., Meyer, R. E. and Rounsaville, B. (1992) Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Archives of General Psychiatry 49, 881887.[Abstract]
O'Malley, S. S., Jaffe, A. J., Chang, G., Rode, S., Schottenfeld, R., Meyer, R. E. and Rounsaville, B. (1996a) Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Archives of General Psychiatry 53, 217224.[Abstract]
O'Malley, S. S., Jaffe, A. J., Rode, S. and Rounsaville, B. J. (1996b) Experience of a slip among alcoholics treated with naltrexone or placebo. American Journal of Psychiatry 153, 281283.[Abstract]
Obermann, K., Mattias, G., Schulenburg, J. M. and Mautner, G. C. (1997) [Economic analysis of secondary prevention of coronary heart disease with simvastatin (Zocor) in Germany] Okonomische Analyse der Sekundarpravention der koronaren Herzkrankheit mit Simvastatin (Zocor) in Deutschland. Medizinische Klinik 92, 686694.[ISI][Medline]
Paille, F. M., Guelfi, J. D., Perkins, A. C., Royer, R. J., Steru, L. and Parot, P. (1995a) Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol and Alcoholism 30, 239247.[Abstract]
Paille, F., Parot, P. and Gillet, C. (1995b) Contribution of acamprosate in maintaining abstinence in weaned alcohol-dependent patients: additional results of the second French multicentre study. 1st Campral Symposium, ESBRA, held at Stuttgart. Springer, Berlin.
Palliyath, S. K., Schwartz, B. and Grant, L. (1990) Peripheral nerve functions in chronic alcoholic patients on disulfiram: a six month follow up. Journal of Neurology, Neurosurgery and Psychiatry 53, 227230.[Abstract]
Palmer, A. J., Weiss, C., Pommer, W. and Wenzel, H. (1996) The impact of three different management strategies on the development of diabetic nephropathy: a cost-effectiveness analysis for Germany. Medical Decision Making 16, 451.
Palmer, A. J., Weiss, C., Brandt, A., Singh, G. and Wenzel, H. (1999) Cost-effectiveness of intensive therapy for type I diabetes changes depending on risk factors and level of existing complications. Medical Decision Making 17, 528.
Palmer, A. J., Weiss, C., Sendi, P. P., Neeser, K., Singh, G., Wenzel, H. and Spinas, G. A. (2000) The cost-effectiveness of different management strategies for type 1 diabetes: A Swiss perspective. Diabetologia 43, 1326.[ISI][Medline]
Parent, J. and Barkun, A. (1996) Acute pancreatic injury in asymptomatic individuals after heavy drinking over the long-term. Gastrointestinal Endoscopy 43, 637638.[Medline]
Pavan, D., Nicolosi, G. L., Lestuzzi, C., Burelli, C., Zardo, F. and Zanuttini, D. (1987) Normalization of variables of left ventricular function in patients with alcoholic cardiomyopathy after cessation of excessive alcohol intake: an echocardiographic study. European Heart Journal 8, 535540.[Abstract]
Pelc, I., Le Bon, O. and Verbanck, P. (1994) Acamprosate in the treatment of alcohol dependence: a six month post-detoxification study. Alcohol 18, 38A.
Pelc, I., Verbanck, P., Le Bon, O., Gavrilovic, M., Lion, K. and Lehert, P. (1997) Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. a 90-day placebo-controlled dose-finding study. British Journal of Psychiatry 171, 7377.[Abstract]
Pell, S. and D'Alonzo, C. A. (1973) A five-year mortality study of alcoholics. Journal of Occupational Medicine 15, 120125.[Medline]
Pequignot, G., Tuyns, A. J. and Berta, J. L. (1978) Ascitic cirrhosis in relation to alcohol consumption. International Journal of Epidemiology 7, 113120.[Abstract]
Perretti, A., Gentile, S., Balbi, P., Persico, M. and Caruso, P. (1995) Peripheral neuropathy in liver cirrhosis. A clinical and electrophysiological study. Italian Journal of Gastroenterology 27, 349354.[ISI][Medline]
Petry, W., Heintges, T., Hensel, F., Erhardt, A., Wenning, M., Niederau, C. and Haussinger, D. (1997) [Hepatocellular carcinoma in Germany. Epidemiology, etiology, clinical aspects and prognosis in 100 consecutive patients of a university clinic] Hepatozellulares Karzinom in Deutschland. Epidemiologie, Atiologie, Klinik und Prognose bei 100 konsekutiven Patienten einer Universitatsklinik. Zeitschrift für Gastroenterologie 35, 10591067.[ISI][Medline]
Piette, J. D., Barnett, P. G. and Moos, R. H. (1998) First-time admissions with alcohol-related medical problems: a 10-year follow-up of a national sample of alcoholic patients. Journal of Studies on Alcohol 59, 8996.[ISI][Medline]
Poldrugo, F. (1997) Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction 92, 15371546.[ISI][Medline]
Prazak, P., Pfisterer, M., Osswald, S., Buser, P. and Burkart, F. (1996) Differences of disease progression in congestive heart failure due to alcoholic as compared to idiopathic dilated cardiomyopathy. European Heart Journal 17, 251257.[Abstract]
Regan, T. J. (1984) Alcoholic cardiomyopathy. Progress in Cardiovascular Diseases 27, 141152.[ISI][Medline]
Sass, H., Soyka, M., Mann, K. and Zieglgansberger, W. (1996a) Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Archives of General Psychiatry 53, 673680.[Abstract]
Sass, H., Soyka, M., Mann, K. and Zieglgansberger, W. (1996b) Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Archives of General Psychiatry 53, 673680.[Abstract]
Saunders, J. B. and Latt, N. (1993) Epidemiology of alcoholic liver disease. Baillières Clinical Gastroenterology 7, 555579.[ISI][Medline]
Schadlich, P. K. and Brecht, J. G. (1998) The cost effectiveness of acamprosate in the treatment of alcoholism in Germany. Pharmacoeconomics 13, 719730.[ISI][Medline]
Scheld, H. H., Deng, M. C., Hammel, D., Roeder, N. and Roetker, J. (1994) [Cost/benefit relations in heart transplantation] Kosten/ Nutzen-Relation der Herztransplantation. Zeitschrift für Kardiologie 83 (Suppl. 6), 139149.
Schwartz, L., Sample, K. A. and Wigle, D. E. (1975) Severe alcoholic cardiomyopathy reversed with abstention from alcohol. American Journal of Cardiology 36, 963966.[ISI][Medline]
Senft, R. A., Polen, M. R., Freeborn, D. K. and Hollis, J. F. (1997) Brief intervention in a primary care setting for hazardous drinkers. American Journal of Preventive Medicine 13, 464470.[ISI][Medline]
Siegel, J. E., Weinstein, M. C., Russell, L. B. and Gold, M. R. (1996) Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine. Journal of the American Medical Association 276, 13391341.[Abstract]
Sorensen, T. I., Orholm, M., Bentsen, K. D., Hoybye, G., Eghoje, K. and Christoffersen, P. (1984) Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet 2, 241244.[ISI][Medline]
Tamburro, C. H. and Lee, H. M. (1981) Primary hepatic cancer in alcoholics. Clinical Gastroenterology 10, 457477.[ISI][Medline]
Tang, H., Boulton, R., Gunson, B., Hubscher, S. and Neuberger, J. (1998) Patterns of alcohol consumption after liver transplantation. Gut 43, 140145.
Teran, J. C., Imperiale, T. F., Mullen, K. D., Tavill, A. S. and McCullough, A. J. (1997) Primary prophylaxis of variceal bleeding in cirrhosis: a cost-effectiveness analysis. Gastroenterology 112, 473482.[ISI][Medline]
US Department of Health and Human Services, Public Health Service (1996) Cost-effectiveness in health and medicine. Report to the US Public Health Service by the panel on cost-effectiveness in health and medicine. US Government Printing Office, Washington, DC.
Urbistondo, M., Torres, E. A., Castro, F., Oharriz, J., Medina, R., Molina, A., Marquez, E. and Rubio, C. E. (1996) Prevention of recurrent esophageal bleeding and survival in patients with alcoholic cirrhosis: a randomized study. Puerto Rico Health Sciences Journal 15, 195199.[Medline]
Verband Deutscher Rentenversicherungsträger (1996) Statistik Rehabilitation des Jahres 1994. VDR, Frankfurt am Main.
Volpicelli, J. R., Alterman, A. I., Hayashida, M. and O'Brien, C. P. (1992) Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49, 876880.[Abstract]
Volpicelli, J. R., Clay, K. L., Watson, N. T. and O'Brien, C. P. (1995a) Naltrexone in the treatment of alcoholism: predicting response to naltrexone. Journal of Clinical Psychiatry 56 (Suppl. 7), 3944.[ISI][Medline]
Volpicelli, J. R., Watson, N. T., King, A. C., Sherman, C. E. and O'Brien, C. P. (1995b) Effect of naltrexone on alcohol high in alcoholics. American Journal of Psychiatry 152, 613615.[Abstract]
Volpicelli, J. R., Rhines, K. C., Rhines, J. S., Volpicelli, L. A., Alterman, A. I. and O'Brien, C. P. (1997) Naltrexone and alcohol dependence. Role of subject compliance. Archives of General Psychiatry 54, 737742.[Abstract]
Wahl, P., Favier, J. P., Zupan, M., Roul, G. and Sacrez, A. (1985) [Course and prognosis of apparently primary congestive cardiomyopathies in chronic alcoholic patients] Evolution et pronostic des cardiomyopathies congestives d'apparence primitive chez les sujets ethyliques chroniques. Annales de Cardiologie et d'Angeiologie 34, 525530.
Weinstein, M. C., Siegel, J. E., Gold, M. R., Kamlet, M. S. and Russell, L. B. (1996) Recommendations of the Panel on Cost-effectiveness in Health and Medicine. Journal of the American Medical Association 276, 12531258.[Abstract]
Welch, H. G., Albertsen, P. C., Nease, R. F., Bubolz, T. A. and Wasson, J. H. (1996) Estimating treatment benefits for the elderly: the effect of competing risks. Annals of Internal Medicine 124, 577584.
Wetzel, W., Muller, D. and Koch, R. D. (1989) [Regression of autonomic symptoms in alcoholic polyneuropathy] Zur Ruckbildungsfahigkeit vegetativer Symptome bei der alkoholischen Polyneuropathie. Psychiatrie, Neurologie Und Medizinische Psychologie 41, 553555.
Whitworth, A. B., Fischer, F., Lesch, O. M., Nimmerrichter, A., Oberbauer, H., Platz, T., Potgieter, A., Walter, H. and Fleischhacker, W. W. (1996) Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet 347, 14381442.[ISI][Medline]
Wilk, A. I., Jensen, N. M. and Havighurst, T. C. (1997) Meta-analysis of randomized control trials addressing brief interventions in heavy alcohol drinkers. Journal of General Internal Medicine 12, 274283.[ISI][Medline]
Wright, J. C. and Weinstein, M. C. (1998) Gains in life expectancy from medical interventions standardizing data on outcomes. New England Journal of Medicine 339, 380386.
Wright, S., Moran, L., Meyrick, M., O'Connor, R. and Touquet, R. (1998) Intervention by an alcohol health worker in an accident and emergency department. Alcohol and Alcoholism 33, 651656.[Abstract]
www.eurotransplant.nl. Liver transplantation (1997) Internet website accessed June 1999.