Drug Safety

, Volume 25, Issue 10, pp 735–750 | Cite as

A New Poisson and Bayesian-Based Method to Assign Risk and Causality in Patients with Suspected Hepatic Adverse Drug Reactions

A Report of Two New Cases of Ticlopidine-Induced Hepatotoxicity
  • Pedro Zapater
  • José Such
  • Miguel Pérez-Mateo
  • José Francisco Horga
Original Research Article

Abstract

Objective: The diagnosis of drug-induced hepatotoxicity is based on circumstantial evidence and is often inaccurate. We have designed a method based on published data to assign causality to suspected cases of drug-induced hepatotoxicity.

Design: Forty-seven published cases of ticlopidine-induced hepatotoxicity were identified by a Medline-based literature search. Data regarding abnormal liver function in patients receiving ticlopidine were obtained from the only published placebo-ticlopidine clinical trial (the Canadian American Ticlopidine Study; CATS). Thus, we calculated the maximum number of expected hepatotoxicity cases in patients exposed to ticlopidine and those not exposed to the drug by means of the Poisson distribution. The calculated odds ratio was used as a prior odd for subsequent quantification, using a Bayesian-based approach, of individual ticlopidine-induced hepatotoxicity likelihood. Concretely, the prior odd is modified by several separate likelihood ratios: age; sex; AST level; ALT level; alkaline phosphatase level; total bilirubin level; latent period of adverse reaction appearance; and period of remission of adverse reaction. This methodology was applied to two new cases of suspected ticlopidine-induced hepatotoxicity.

Results: The prior probability of ticlopidine-induced hepatotoxicity derived from CATS data is 61.29%. This is in contrast with the 28.83% incidence rate of drug-induced liver alterations in the general population. Alkaline phosphatase levels and total bilirubin levels were six times the normal values among individuals with ticlopidine-induced hepatotoxicity than in the general population. They were the most relevant likelihood ratios of the Bayesian model to establish a high level of causality relationship between a hepatotoxicity event and ticlopidine use.

Conclusions: The proposed method, which links information from clinical trials with the profile of clinical hepatotoxicity of a drug defined from published cases reported after a drug is marketed, can be a useful tool for drug postmarketing surveillance research.

References

  1. 1.
    Nies AS, Spielberg SP. Principles of therapeutics. In: Hardman JG, Gilman AG, Limbird LE, editors. Goodman & Gilman’s The pharmacological basis of therapeutics. New York: McGraw-Hill, 1996: 43–62Google Scholar
  2. 2.
    Avorn J. Reporting drug side effects: signals and noise [editorial]. JAMA 1990; 263: 1823PubMedCrossRefGoogle Scholar
  3. 3.
    Juergens J. Controversies in adverse drug reaction reporting. Am J Hosp Pharm 1990; 47: 76–7PubMedGoogle Scholar
  4. 4.
    Mamelok RD. Drug discovery and development. In: Melmon KL, Morrelli HF, Hoffman BB, Nierenberg DW, editors. Clinical pharmacology: basic principles in therapeutics. New York: McGraw-Hill, 1992: 911–21Google Scholar
  5. 5.
    Vasco AJ M, Rui MM V. Development and Validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26: 664–9CrossRefGoogle Scholar
  6. 6.
    Zimmerman HJ, Ishak KG. General aspects of drug-induced liver disease. Gastroenterol Clin North Am 1995; 24: 739–57PubMedGoogle Scholar
  7. 7.
    Duh M, Walker AM, Kronlund KH. Descriptive epidemiology of acute liver enzyme abnormalities in the general population of Central Massachusetts. Pharmacoepidemiol Drug Saf 1999; 8: 275–83PubMedCrossRefGoogle Scholar
  8. 8.
    Saltiel E, Ward A. Ticlopidine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease status. Drugs 1987; 34(2): 222–62PubMedCrossRefGoogle Scholar
  9. 9.
    Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; I: 1215–20CrossRefGoogle Scholar
  10. 10.
    Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990; 227: 301–8PubMedCrossRefGoogle Scholar
  11. 11.
    Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–7PubMedCrossRefGoogle Scholar
  12. 12.
    Carvajal A, García P, Rueda AM, et al. Ticlopidina y reacciones adversas hepáticas. Datos recogidos por el Sistema Español de Farmacovigilancia [letter]. Med Clin (Barc) 1999; 112: 557–8Google Scholar
  13. 13.
    Deschamps JP, Lassègue A, Ottingnon Y, et al. Lètere cholestatique associé a la prise de ticlopidine: a propose de deux premier cas. Gastroenterol Clin Biol 1982; 6: 595–6PubMedGoogle Scholar
  14. 14.
    Biour M, Poupon R, Grangè JD, et al. Hèpatotoxicitè des medicaments. 11e mise à jour du fichier bibliographique des atteintes hèpatiques et des mèdicaments responsables. Gastroenterol Clin Biol 1998; 22: 1004–44PubMedGoogle Scholar
  15. 15.
    Iqbal M, Goenka P, Young MF, et al. Ticlopidine-induced cholestatic hepatitis. Report of three cases and review of the literature. Dig Dis Sci 1998; 43: 2223–6PubMedCrossRefGoogle Scholar
  16. 16.
    López P, Castiella A, Bujanda L, et al. Hepatitis colestásica por ticlopidina. Presentación de un nuevo caso. Rev Esp Enferm Dig 1995; 87: 735–7PubMedGoogle Scholar
  17. 17.
    Martínez A, De Arce A, Castiella A, et al. Hepatotoxicity due to ticlopidine. Ann Pharmacol 1998; 32: 1250–1CrossRefGoogle Scholar
  18. 18.
    Begaud B, Moride Y, Tubert-Bitter P, et al. False-positives in spontaneous reporting: should we worry about them? Br J Clin Pharmacother 1994; 38: 401–4CrossRefGoogle Scholar
  19. 19.
    Stricker BHCh. Diagnosis and causality assessment of drug-induced hepatic injury. In: Stricker BHCh, editor. Drug-induced hepatic injury. Amsterdam: Elsevier, 1992: 1–14Google Scholar
  20. 20.
    Haramburu F, Fourrier A, Pèrè J, et al. Estimation of the numerator in spontaneous reporting. In: Bégaud B, Chaslerie A, Forrester A, et al, editors. Methodological approaches in pharmacoepidemiology. Post Marketing Surveillance no. 7 (special issue). Amsterdam; Elsevier Science, 1993: 27–37Google Scholar
  21. 21.
    Laposata M. The N Engl J Med, SI unit conversion guide. In: Laposata M, editor. The N Engl J Med SI unit conversion guide. Boston (MA): Massachusets Medical Society, 1992: 56–62Google Scholar
  22. 22.
    Schenker S, Martin R, Hoyumpa A. Antecedent liver disease and drug toxicity. J Hepatol 1999; 31: 1098–105PubMedCrossRefGoogle Scholar
  23. 23.
    Naranjo CA, Kwok MCO, Lanctôt KL, et al. Enhanced differential diagnosis of anticonvulsant hypersensitivity reactions by an integrated bayesian and biochemical approach. Clin Pharmacol Ther 1994; 56: 564–75PubMedCrossRefGoogle Scholar
  24. 24.
    Girardin SM, Cordonnier C. Letère cholestatique et agranulocytose dus à la ticlopidine. Gastroenterol Clin Biol 1982; 6: 716–7Google Scholar
  25. 25.
    Biour M, Toussaint P, Duhamel G, et al. Ticlopidine: atteintes sanguines et hepatiques? Therapie 1982; 37: 217–24Google Scholar
  26. 26.
    Eugene C, Lefebvre JF, Gury B, et al. Hépatite cholestiatique: role vraisemblable de la ticlopidine. Sem Hop 1983; 59: 2923–4PubMedGoogle Scholar
  27. 27.
    Pistone AM, Podesta F, Raviolo E, et al. Nyffeneger: epatosteatosi colestatica di probabile origine iatrogena. Recenti Prog Med 1986; 77: 188–90PubMedGoogle Scholar
  28. 28.
    Miyahara K, Kasahara N, Kondo Y, et al. Changes in plasma lipids and abnormal lipoproteins in a patient with drug-induced cholestatic hepatitis. Jpn J Med 1991; 30: 354–9PubMedCrossRefGoogle Scholar
  29. 29.
    Mammarella A, Paoletti V, Moroni C, et al. Ittero colestatico da ticiopidina. Clin Ther 1991; 138: 45–6Google Scholar
  30. 30.
    Sondag D, Bader R, Clande P, et al. Hèpatite a la ticiopidine: un nouveau cas [letter]. Ann Gastroenterol Hepatol (Paris) 1993; 29: 40–1Google Scholar
  31. 31.
    Greany Jr JJ, Hess DA, Mahoney C: Ticlopidine-induced cholestatic jaundice [letter]. Clin Pharm 1993; 12: 398–9PubMedGoogle Scholar
  32. 32.
    Nurhussein MA: Ticlopidine-induced prolonged cholestasis [letter]. J Am Geriatr Soc 1993; 41: 1371–2PubMedGoogle Scholar
  33. 33.
    Elizaga Corrales JE, Herraez AM, Cejudo DR: Ictericia colestásica secundaria a ticlopidina [letter]. An Med Interna 1993; 10: 621–2PubMedGoogle Scholar
  34. 34.
    Grimm IS, Litynski JJ. Severe cholestasis associated with ticlopidine. Am J Gastroenterol 1994; 89: 279–80PubMedGoogle Scholar
  35. 35.
    Yoder JD, Algozzine GJ, Hill GW: More ticlopidine-induced cholestatic jaundice [letter]. Am J Hosp Pharm 1994; 51: 1821–2PubMedGoogle Scholar
  36. 36.
    Weber E, Donckier J. Ictère cholestatique sur ticlopidine: Un nouveau cas. Acta Clin Belg 1994; 49: 309–10PubMedGoogle Scholar
  37. 37.
    Colvicchi F, Magnanimi S, Sebastiani F, et al. Ticlopidine-induced chronic cholestasic hepatitis: a case report. Curr Ther Res Clin Exp 1994; 55: 929–31CrossRefGoogle Scholar
  38. 38.
    Alvaro D, Gigliozzi A, Gaudio E, et al. Ticlopidine-induced cholestasis: report of two cases and experimental evidence of the drugs adverse effect in isolated perfused rat liver. Eur J Gastroenterol Hepatol 1994; 6: 943–50CrossRefGoogle Scholar
  39. 39.
    Cassidy LJ, Schuster BG, Halparin LS. Probable ticlopidine induced cholestatic hepatitis. Ann Pharmacother 1995; 29: 30–1PubMedGoogle Scholar
  40. 40.
    Ruiz-Valverde P. Ticlopidine-induced granulomatous hepatitis [letter]. Ann Pharmacother 1995; 29: 633–4PubMedGoogle Scholar
  41. 41.
    Roy L, Plante M-A, Perreault H, et al. Cholestatic hepatitis: Ticlopidine suspected. Therapie 1995; 50: 587–95Google Scholar
  42. 42.
    Naschitz JE. Khamessi R, Elias N, et al. Ticlopidine induced prolonged cholestasis [letter]. Clin Toxicol 1995; 33: 379–80CrossRefGoogle Scholar
  43. 43.
    Miras-Parra FJ, Gómez-Jiménez FJ, Garcia-Contreras T, et al. Hepatitis colestática por ticlopidina. Rev Esp Enferm Dig 1995; 87: 414–5PubMedGoogle Scholar
  44. 44.
    Alberto L, Queiroz H, Gonzalez C, et al. Hepatoxicidade pela ticlopidina. Arq Med (Brazil) 1995; 9: 115–6Google Scholar
  45. 45.
    Pascual S, Sarrion JV, Jarque I, et al. Hepatitis colestasica y anemia por ticlopidina. Gastroenterol Hepatol 1996; 19: 208–9PubMedGoogle Scholar
  46. 46.
    Díaz-Fuenzalida A, Valdés Socin H, Laudano O, et al. Colestasis asociada a ticlopidina. Gastroenterol Hepatol 1997; 20: 128–30PubMedGoogle Scholar
  47. 47.
    Bruguera M. Hepatitis colestásica asociada a ticlopidina. Gastroenterol Hepatol 1997; 20: 163–4PubMedGoogle Scholar
  48. 48.
    Yim HB, Lieu PK, Choo PW. Ticlopidine-induced cholestatic jaundice. Singapore Med J 1997; 38: 132–3PubMedGoogle Scholar
  49. 49.
    Guzzini F, Banfi L, Gomitoni A, et al. Due casi di colestasi acuta da ticlopidina. Recenti Prog Med 1997; 88: 124–7PubMedGoogle Scholar
  50. 50.
    Artímez ML, Fernández E, Rodriguez M, et al. Hepatitis tóxica por ticlopidina. Tres nuevos casos. Rev Esp Enferm Dig 1997; 89: 796–7PubMedGoogle Scholar
  51. 51.
    Sanjuan F, Jimenez J, Naya J, et al. Hepatitis colestásica por ticlopidina: presentación de un nuevo caso. Ann Med Interna 1997; 14: 78–9Google Scholar
  52. 52.
    Sossai P. Liver injury with the use of ticlopidine [letter]. Ann Pharmacother 1998; 32: 1370PubMedCrossRefGoogle Scholar
  53. 53.
    Wegmann C, Munzenmaier R, Dormann AJ, et al. Ticlopidine-induced acute cholestatic hepatitis. Dtsch Med Wochenschr 1998; 123: 146–50PubMedCrossRefGoogle Scholar
  54. 54.
    Grieco A, Vecchio FM, Greco AV, et al. Cholestatic hepatitis due to ticlopidine: clinical and histological recovery after drug withdrawal. Case report and review of the literature. Eur J Gastroenterol Hepatol 1998; 10: 7143–5Google Scholar
  55. 55.
    Meyer MI, Kuhn M, Buhler H, et al. Ticlopidine-induced cholestasis. Schweiz Med Wochenschr 1999; 129: 1405–9PubMedGoogle Scholar
  56. 56.
    Kubin CJ, Sherman O, Hussain KB, et al. Delayed-onset ticlopidine-induced cholestatic jaundice. Pharmacotherapy 1999; 19: 1006–10PubMedCrossRefGoogle Scholar
  57. 57.
    Amaro P, Nunes A, Macoas F, et al. Ticlopidine-induced prolonged cholestasis: a case report. Eur J Gastroenterol Hepatol 1999; 11: 673–6PubMedCrossRefGoogle Scholar
  58. 58.
    Danan G. Liver test abnormalities. In: Bénichou C, editor. Adverse drug reactions. A practical guide to diagnosis and management. Chichester: John Wiley & Sons Ltd, 1994: 3–12Google Scholar
  59. 59.
    Stricker BHCh, Biour M, Wilson JHP. Anticonvulsant and antiparkinsonian agents. In: Stricker BHCh, editor. Drug-induced hepatic injury. Amsterdam: Elsevier, 1992: 150–67Google Scholar
  60. 60.
    The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–71Google Scholar
  61. 61.
    Golbe LI. Long-term efficacy and safety of deprenyl (selegiline) in advanced Parkinson’s disease. Neurology 1989; 39: 1109–11PubMedCrossRefGoogle Scholar
  62. 62.
    Pratts DS, Marshall M, Kaplan MD. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000; 342: 1266–71CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Pedro Zapater
    • 1
  • José Such
    • 2
  • Miguel Pérez-Mateo
    • 2
  • José Francisco Horga
    • 1
  1. 1.Clinical Pharmacology UnitUniversity General Hospital of Alicante and Department of Pharmacology and Therapeutics, Faculty of Medicine, University Miguel HernándezSan Juan de AlicanteSpain
  2. 2.Liver Unit, Department of MedicineUniversity General Hospital of Alicante and Department of Medicine, Faculty of Medicine, University Miguel HernándezSan Juan de AlicanteSpain

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