D‐penicillamine for primary biliary cirrhosis

Yan Gong; Sarah Louise Klingenberg; Christian Gluud

doi:10.1002/14651858.CD004789.pub2

D‐penicilamina para la cirrosis biliar primaria

Contraer todo Desplegar todo

Referencias

Referencias de los estudios incluidos en esta revisión

Ir a:

estudios excluidos
otras referencias
otras versiones publicadas

Bassendine MF, Macklon AF, Mulcahy R, James OFW. Controlled trial of high and low dose D‐penicillamine (DP) in primary biliary cirrhosis (PBC): results at three years (abstract). Gut 1982;23:A909.

Google Scholar

Macklon AF, Bassendine MF, James OFW. Controlled trial of D‐penicillamine in primary biliary cirrhosis: incidence of side effects and relation to dose (IASL abstract). Hepatology 1982;2:166.

Google Scholar

Bodenheimer HC, Charland C, Thayer WR, Schaffner F, Staples PJ. Immunologic effects of penicillamine in patients with primary biliary cirrhosis. Hepatology 1983;3:845.

Google Scholar

Bodenheimer HC, Colette CJr, Thayer WR, Schaffner FJr, Staples PJ. Effects of penicillamine on serum immunoglobulins and immune complex‐reactive material in primary biliary cirrhosis. Gastroenterology 1985;88:412‐7.

Bodenheimer HC, Schaffner F, Sternlieb I, Klion FM, Vernace S, Pezzullo J. A prospective clinical trial of D‐penicillamine in the treatment of primary biliary cirrhosis. Hepatology 1985;5(6):1139‐42.

Schaffner F, Sternlieb I, Sachs H. A two dose level randomized double blind controlled trial of penicillamine in primary biliary cirrhosis. Hepatology 1982;2(5):168.

Google Scholar

Deering TB, Dickson ER, Fleming CR, Geall MG, McCall JT, Baggenstoss AH. Effect of D‐penicillamine on copper retention in patients with primary biliary cirrhosis. Gastroenterology 1977;72:1208‐12.

Dickson ER. The syndrome of primary biliary cirrhosis. Journal of Rheumatology 1981;8(Suppl 7):121‐3.

Google Scholar

Dickson ER, Fleming TR, Wiesner RH, Baldus WP, Fleming CR, Ludwig J, et al. Trial of penicillamine in advanced primary biliary cirrhosis. New England Journal of Medicine 1985;312(16):1011‐5. [MEDLINE: 85163601]

Dickson ER, Wiesner RH, Baldus WP, Fleming CR, Ludwig JL. D‐penicillamine improves survival and retards histologic progression in primary biliary cirrhosis (abstract). Gastroenterology 1982;82:1225.

Google Scholar

Locke GR, Therneau TM, Lugwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology 1996;23:52‐6.

Powell FC, Dickson ER. Primary biliary cirrhosis and lichen planus. Journal of the American Academy of Dermatology 1983;9(4):540‐5.

Reed M. Penicillaine therapy 'encouraging' in primary biliary cirrhosis study. JAMA 1982;248:11‐2.

Epstein O, Cook DG, Jain S, McIntyre N, Sherlock S. D‐penicillamine and clinical trials in PBC (AASLD abstract). Hepatology 1984;4:1032.

Google Scholar

Epstein O, Cook DG, Jain S, Sherlick S. D‐penicillamine in primary biliary cirrhosis (PBC) ‐ an untested (and untestable?) treatment (abstract). Gut 1984;25:A1134.

Google Scholar

Epstein O, Jain S, Lee RG, Cook DG, Boss AM, Scheuer PJ, Scherlock S. D‐penicillamine treatment improves survival in primary biliary cirrhosis (abstract). Gut 1981;22:A433.

Google Scholar

Epstein O, Jain S, Lee RG, Cook DG, Boss AM, Scheuer PJ, et al. D‐penicillamine treatment improves survival in primary biliary cirrhosis. Lancet 1981;1:1275‐7.

Epstein O, Villiers DD, Jain S, Potter B, Thomas H, Sherlock S. Reduction of immune complexes and immunoglobulins induced by D‐penicillamine in primary biliary cirrhosis. The New England Journal of Medicine 1979;300:274‐8.

Epstein O, Villiers DD, Jain S, Potter BJ, Thomas HC, Sherlock S. Effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis (PBC) (abstract). Gut 1978;19:A994.

Google Scholar

Jain S, McGee JO'D, Scheuer PJ, Samourian S, Sherlock S. A controlled trial of D‐penicillamine therapy in primary biliary cirrhosis and chronic active hepatitis (abstract). Digestion 1976;14:523.

Google Scholar

Jain S, Scheuer PJ, Samourian S, McGee J, Sherlock S. A controlled trial of D‐penicillamine therapy in primary biliary cirrhosis. Lancet 1977;16:831‐4.

Jain S, Scheur PJ, Samourian S, McGee JO'D, Sherlock S. A controlled trial of D‐penicillamine therapy in primary biliary cirrhosis (abstract). Gut 1976;17:822.

Google Scholar

Matloff DS, Alpert E, Resnick RH, Kaplan MM. A prospective trial of D‐penicillamine in primary biliary cirrhosis. New England Journal of Medicine 1982;306(6):319‐26. [MEDLINE: 82103912]

Matloff DS, Resnick RH, Alpert E, Kaplan M. D‐penicillamine does not alter the course of primary biliary cirrhosis (abstract). Clinical Research 1979;27:579A.

Google Scholar

Neuberger J, Christensen E, Popper H, Portmann B, Caballeri J, Rodes J, et al. D‐penicillamine in primary biliary cirrhosis: preliminary results of an international trial (EASL abstract). Liver 1984;4:G31.

Google Scholar

Neuberger J, Christensen E, Popper H, Portmann B, Caballeri J, Rodes J, et al. D‐penicillamine in primary biliary cirrhosis: preliminary results of an international trial (abstract). Gut 1983;24:A968.

Google Scholar

Neuberger J, Christensen E, Portmann B, Caballeria J, Rodes J, Ranek L, et al. Double blind controlled trial of D‐penicillamine in patients with primary biliary cirrhosis. Gut 1985;26(2):114‐9. [MEDLINE: 85102903]

Taal BG, Schalm SW. Cryoglobulins in primary biliary cirrhosis: prevalence and modulation by immunosuppressive therapy. Zeitschrift für Gastroenterologie 1985;23:228‐34.

Taal BG, Schalm SW. Prednisone plus D‐penicillamine, D‐penicillamine and placebo compared in primary biliary cirrhosis syndrome (abstract). Gastroenterology 1981;80:1351.

Google Scholar

Taal BG, Schalm SW, Ten Kate FWJ, Henegouwen GPB, Brandt KH. Low therapeutic value of D‐penicillamine in a short‐term prospective trial in primary biliary cirrhosis. Liver 1983;3:345‐52.

Taal BG, Schalm SW, Ten Kate FWJ, Van Berge Henegouwen GP, Brandt KH. A double‐blind controlled trial of D‐penicillamine for PBC: the dose dependent effect (abstract) [Een dubbelblind onderzoek met een controlegroep met D‐penicillamine bij primaire biliaire cirrose: van de dosis afhankelijke effecten]. Nederlands Tijdschrift voor Geneeskunde 1982;126:547.

Google Scholar

Referencias de los estudios excluidos de esta revisión

Ir a:

estudios incluidos
otras referencias
otras versiones publicadas

Gupta RC, Dickson ER, McDuffie FC, Baggenstoss AH. Immune complexes in primary biliary cirrhosis: high prevalence of circulating immune complexes in patients with associated autoimmune features. American Journal of Medicine 1982;73(2):192‐8.

Savolainen ER, Miettinen TA, Pikkarainen P, Salaspuro MP, Kivirikko KI. Enzymes of collagen synthesis and type III procollagen aminopropeptide in the evaluation of D‐penicillamine and medroxyprogesterone treatments of primary biliary cirrhosis. Gut 1983;24:136‐42.

Triger DR, Manifold IH, Cloke P, Underwood JCE. D‐penicillamine in primary biliary cirrhosis: two year results of a single centre, double‐blind controlled trial. Gut 1980;21(9):A919‐20.

Google Scholar

Referencias adicionales

Ir a:

estudios incluidos
estudios excluidos
otras versiones publicadas

Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers' Handbook 4.2.1[updated December 2003]. The Cochrane Library 2004, Issue 1.

Google Scholar

Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326:219.

Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor KD, Dickson ER. Diminished survival in asymptomatic primary biliary cirrhosis: a prospective study. Gastroenterology 1990;98:1567‐71. [MEDLINE: 90249649]

Ballardini G, Mirakian R, Bianchi FB, Pisi E, Doniach D, Bottazzo GF. Aberrant expression of HLA‐DR antigens on bile duct epithelium in primary biliary cirrhosis: relevance to pathogenesis. Lancet 1984;ii:1009. [MEDLINE: 85035466]

Google Scholar

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088‐1101.

Beswick DR, Klatskin G, Boyer JL. Asymptomatic primary biliary cirrhosis: a progress report on long‐term follow‐up and natural history. Gastroenterology 1985;89:267‐71. [MEDLINE: 85231878]

Christensen E, Neuberger J, Crowe J, Altman DG, Popper H, Portmann B, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology 1985;89:1084‐91. [MEDLINE: 86006138]

Deeks JJ, Altman DG. Effect measures for meta‐analysis of trials with binary outcomes. In: Egger M, Davey Smith G, Altman DG editor(s). Systematic Reviews in Health Care: Meta‐Analysis in Context. Second Edition. London: BMJ Books, 2001.

Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examing heterogeneity and combing results from several studies in meta‐analysis. In: Egger M, Davey Smith G, Altman DG editor(s). Systematic Reviews in Health Care: Meta‐analysis in Context. Second Edition. London: BMJ Books, 2001.

Deeks JJ. Issues in the selection of a summary statistic for meta‐analysis of clinical trials with binary outcomes. Statistics in Medicine 2002;21:1575‐1600.

Deiss A, Lynch RE, Lee GR, Cartwright GE. Long term therapy of Wilson's disease. Annals of Internal Medicine 1971;75:57‐65.

DeMets DL. Methods of combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50. [MEDLINE: 87291426]

DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88. [MEDLINE: 87104256]

Egger M, Smith GD, Schneider M, Minder C. Bias in meta‐analysis detected by a simple graphical test. BMJ 1997;315(7109):629‐34. [MEDLINE: 97456606]

Epstein O, De Villiers D, Jain S, Potter BJ, Thomas HC, Sherlock S. Reduction of immune complexes and immunoglobulins induced by D‐penicillamine in primary biliary cirrhosis. New England Journal of Medicine 1979;300:274‐8.

Epstein O, Chapman RWG, Lake‐Bakaar G, Foo AY, Rosalki SB, Sherlock S, et al. The pancreas in primary biliary cirrhosis and primary sclerosing cholangitis. Gastroenterology 1982;83(6):1177‐82.

Fregeau D, Van de Water J, Danner D, Ansart T, Coppel R, Gershwin M. Antimitochondrial antibodies of primary biliary cirrhosis recongnize dihydrolipoamide acyltransferase and inhibit enzyme function of the branched chain alpha ketoacid dehydrogenase complex. Journal of Immunology 1989;142(11):3815‐20. [BC86215 Hominidae]

Google Scholar

Glasziou PP, Sanders SL. Investigating causes of heterogeneity in systematic reviews. Statistics in Medicine 2002;21:1503‐11.

Gluud C, Afroudakis AP, Caballeria J, Laskus T, Morgan M, Rueff B, et al. Diagnosis and treatment of alcoholic liver disease in Europe ‐ First Report by the Gastroenterology Across Frontiers Panel. Gastroenterology International 1993;6:221‐30.

Google Scholar

Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis. The Cochrane Library 2002, Issue 2.

Google Scholar

Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic‐acid therapy for primary biliary cirrhosis: a meta‐analysis. Lancet 1999;354:1053‐60.

Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology 1976;70(5 Pt. 1):656‐60. [MEDLINE: 76165921]

Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in Medicine 2002;21:1539‐58.

Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. British Medical Journal 1999;319:670‐4.

Hoofnagle JH, Davis GL, Schafer DF, Peters M, Avigan MI, Pappas SC, et al. Randomized trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1986;91(6):1327‐34. [MEDLINE: 87031329]

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Code of Federal Regulation & ICH Guidelines. Media: PAREXEL BARNETT, 1997.

Invernizzi P, Crosignani A, Battezzati PM, Covini G, De‐Valle G, Larghi A, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody‐positive and negative primary biliary cirrhosis. Hepatology 1997;25(5):1090‐5. [MEDLINE: 97286255]

Ioannidis JPA, Lau J. Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses. Proceedings of the National Academy of Sciences of the United States of America 2001;98(3):831‐6.

James O, Macklon AF, Waston AJ. Primary biliary cirrhosis ‐ a revised clinical spectrum. Lancet 1981;1(8233):1278‐81.

Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low‐dose weekly methotrexate. Gastroenterology 1991;101(5):1332‐8. [MEDLINE: 92038733]

Kaplan MM. Primary biliary cirrhosis ‐ a first step in prolonging survival. New England Journal of Medicine 1994;330(19):1386‐7. [MEDLINE: 94203249]

Kaplan MM. Primary biliary cirrhosis. New England Journal of Medicine 1996;335(21):1570‐80.

Kim WR, Lindor KD, Locke GR, Therneau TM, Homburger HA, Batts KP, et al. Epidemiology and natural history of primary biliary cirrhosis in a U.S. community. Gatroenterology 2000;119:1631‐6.

Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9.

Lacerda MA, Ludwig J, Dickson ER, Jorgensen RA, Lindor KD. Antimitochondrial antibody‐negative primary biliary cirrhosis. American Journal of Gastroenterology 1995;90(2):247‐9. [MEDLINE: 95149944]

Google Scholar

Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995;22(4 Pt 1):1158‐62. [MEDLINE: 96029425]

Lipsky PE, Ziff M. Inhibition of human helper T cell function in vitro by D‐penicillamine and copper sulfate. Journal of Clinical Investigation 1980;65:1069‐76.

Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta‐analysis. Statistics in Medicine 2001;20:641‐54.

Mattalia A, Quaranta S, Leung PS, Bauducci M, Van‐de‐Water J, Calvo PL. Characterization of antimitochondrial antibodies in health adults. Hepatology 1998;27(3):656‐61. [MEDLINE: 98160326]

Metcalf J, Mitchison H, Palmer J, Jones D, Bassendine M, James O. Natural history of early primary biliary cirrhosis. Lancet 1996;348(9039):1399‐402. [MEDLINE: 97091611]

Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three‐year results. Journal of Hepatology 1992;15(3):336‐44. [MEDLINE: 93077929]

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13. [MEDLINE: 98417104]

Nimni ME, Deshmukh K, Gerth N. Collagen defect induced by D‐penicillamine. Nature 1972;240:220‐1.

Google Scholar

Nyberg A, Loof L. Primary biliary cirrhosis: clinical features and outcome, with special reference to asymptomatic disease. Scandinavian Journal of Gastroenterology 1989;24(1):57‐64. [MEDLINE: 89186599]

Poupon RE, Huet PM, Poupon R, Bonnand AM, Nhieu JT, Zafrani ES, et al. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1996;24(5):1098‐103. [MEDLINE: 97060347]

Prince M, Jones D, Metcalf J, Craig W, James O. Symptom development and prognosis of initially asymptomatic PBC. Hepatology 2000;32(4 Pt2):171A.

Google Scholar

Prince M, Chetwynd A, Newman W, Metcalf JV, James OFW. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow‐up for up to 28 years. Gatroenterology 2002;123:1044‐51.

Scheuer P. Primary biliary cirrhosis. Proceedings of the Royal Society of Medicine 1967;60(12):1257‐60. [MEDLINE: 68090739]

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. [MEDLINE: 95123716]

Sternlieb I, Scheinberg IH. Penicillamine therapy for hepatolenticular degeneration. JAMA 1964;189:748‐54.

Turchany JM, Uibo R, Kivik T, Van‐de‐Water J, Prindiville T, Coppel RL, et al. A study of antimitochondrial antibodies in a random population in Estonia. American Journal of Gastroenterology 1997;92(1):124‐6. [MEDLINE: 97149143]

Google Scholar

Van den Oord JJ, Sciot R, Desmet VJ. Expression of MHC products by normal and abnormal bile duct epithelium. Journal of Hepatology 1986;3(3):310‐7. [MEDLINE: 87167400]

Verma A, Jazrawi RP, Ahmed HA, Northfield TC. Prescribing habits in primary biliary cirrhosis: a national survey. European Journal of Gastroenterology and Hepatology 1999;11(8):817‐20. [MEDLINE: 99442295]

Vuoristo M, Farkkila M, Karvonen AL, Leino R, Lehtola J, Makinen J, et al. A placebo‐controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid [see comments]. Gastroenterology 1995;108(5):1470‐8. [MEDLINE: 95246981]

Warnes TW, Smith A, Lee FI, Haboubi NY, Johnson PJ, Hunt L. A controlled trial of colchicine in primary biliary cirrhosis: trial design and preliminary report. Journal of Hepatology 1987;5(1):1‐7. [MEDLINE: 88008957]

Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. New England Journal of Medicine 1990;322(20):1419‐24. [MEDLINE: 90231366]

Yamada G, Hyodo I, Tobe K, Mizuno M, Nishihara T, Kobayashi T, et al. Ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelia in primary biliary cirrhosis. Hepatology 1986;6(3):385‐91. [MEDLINE: 86222190]

Referencias de otras versiones publicadas de esta revisión

Ir a:

estudios incluidos
estudios excluidos
otras referencias

Gong Y, Klingenberg L, Gluud C. D‐penicillamine vs placebo/no intervention in patients with primary biliary cirrhosis. Evidence‐Based Gastroenterology 2007;8(2):41‐2.

Google Scholar

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Bassendine 1982

Methods	Generation of allocation sequence: unclear. Allocation concealment: unclear. Blinding: not performed. Follow‐up: adequate, four patients in the high‐dose D‐penicillamine, five patients in the low‐dose D‐penicillamine, and none in control were lost to follow‐up.
Participants	Country: UK. Mean age: not reported. Female/Male: not reported. PBC stage status: not reported.
Interventions	D‐penicillamine 1g/day (n = 19) D‐penicillamine 250 mg/day (n = 22) No intervention (n = 19) Mean period of follow‐up: 37 months. Analysed duration of trial: 3 years.
Outcomes	1. Mortality. 2. Liver biochemical variables. 3. Adverse events.
Notes	1. Side effects required withdrawal of D‐penicillamine in nine patients. 2. It was only published as an abstract. 3. Correspondence sent to the author on 2 December 2003. No reply was received by 20 June 2004.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Bodenheimer 1985

Methods	Generation of allocation sequence: unclear. Allocation concealment: unclear. Blinding: adequate, identical placebo. Follow‐up: inadequate, 26 patients in both groups were lost to follow‐up.
Participants	Place: USA. Mean age: 52 in high‐dose group and the same in low‐dose group. Female/Male:51/5. PBC stage status: 10 with stage I or II in high‐dose group; 8 with stage I or II in low‐dose group. 20 with stage III or IV in high dose group; 18 with stage III or IV in low dose group. Inclusion criteria: 1. A history of chronic cholestatic liver disease. 2. Liver biopsies were compatible with PBC.
Interventions	High‐dose group (n = 30): 250 mg/day increased gradually until 750 mg/day was achieved. Low‐dose group (n = 26): 250 mg/day. Mean period of treatment and follow‐up: three years.
Outcomes	1. Mortality data (only total number for two groups). 2. Liver test results. 3. Liver biopsy findings. 4. Adverse effects.
Notes	1. Liver test results were analysed as logarithms due to log‐normal distribution of data and reported as per cent change. Therefore, it is not possible for us to extract the data. 2. Correspondence sent to the author on 2 December 2003. Reply was received on 13 February 2004. No additional information were added.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	D ‐ Not used

Dickson 1985

Methods	Generation of allocation sequence: adequate, a table of random numbers. Allocation concealment: adequate, a central pharmacist. Blinding: adequate, identical placebo. Follow‐up: adequate, 24 patients in the D‐penicillamine and no patient in the placebo group withdrew from this trial.
Participants	Country: USA. Mean age: not reported, but 43% patients in D‐penicillamine and 54% in placebo not older than 50 years. Female/Male: 200/27. PBC stage status: 3 and 4. Inclusion criteria: 1. Established liver disease of more than six months' duration. 2. Raised alkaline phosphatases more than 2.5 times the normal level. 3. AMA titer greater than 1:10. 4. Liver biopsy diagnostic of, or consistent with PBC.
Interventions	D‐penicillamine 250 mg/day for 2 weeks increased by 250 mg/day every 2 weeks until 1 g/day (n = 111) Placebo (the administration same as D‐penicillamine) (n = 116) Median period of follow‐up: 5 years. Analysed duration of trial: 10 years.
Outcomes	1. Survival analysis. 2. Clinical and biochemical changes. 3. Histologic results. 4. Toxicity.
Notes	1. Survival data at 5 years were available to be extracted only. 2. Correspondence sent to the author on 2 December 2003. No reply was received by 20 June 2004.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Epstein 1981

Methods	Generation of allocation sequence: unclear. Allocation concealment: unclear. Blinding: adequate, identical placebo. Follow‐up: inadequate.
Participants	Country: UK. Mean age: not reported, instead, median age: 52 years in D‐penicillamine, 54 years in placebo. Female/Male: not reported. PBC stage status: 18 with stage 1 or 2 and 37 with stage 3 or 4 in D‐penicillamine; 9 with stage 1 or 2 and 23 with stage 3 or 4 in placebo. Inclusion criteria: 1. Liver test pointed to cholestasis. 2. AMA test positive. 3. Normal extrahepatic bile ducts by cholangiography. 4. Liver histology either diagnostic of or highly suggestive of PBC.
Interventions	D‐penicillamine: over 8 to 10 weeks from 150 mg/day to 600 mg/day (n = 61). Placebo (n = 37). Median period follow‐up: 33 months. Analysed duration of trial: 6 years.
Outcomes	1. Survival data. 2. Liver biochemical variables. 3. Liver histology.
Notes	1. The trial has recruited 98 patients, but data on adverse events were only reported for 87 patients (55 in D‐penicillamine and 32 in placebo group). 2. Because of expected withdrawals due to D‐penicillamine drug reactions, the randomisation was weighted to allow a 3:2 ratio of D‐penicillamine to placebo treated patients. 2. Correspondence sent to the author on 2 December 2003. No reply was received by 20 June 2004.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Matloff 1982

Methods	Generation of allocation sequence: unclear. Allocation concealment: adequate, a study monitor. Blinding: adequate, identical placebo. Follow‐up: adequate, nine patients in the D‐penicillamine group and no patients in the placebo group were lost to follow‐up.
Participants	Country: USA. Mean age: 51.5 years in D‐penicillamine, 51.5 years in placebo. Female/Male: 48 /4. PBC stage status: 14 patients with advanced disease in D‐penicillamine, 13 in placebo. Inclusion criteria: 1. A history of chronic cholestatic liver disease. 2. Raised alkaline phosphatases. 3. patent extrahepatic bile ducts. 4. Liver specimen diagnostic of or consistent with primary biliary cirrhosis. 5. AMA test positive.
Interventions	D‐penicillamine 1g/day (n = 26). Placebo: identical placebo (n = 26). Total treatment duration: 28 months.
Outcomes	1. Survival data. 2. Liver histology. 3. Liver biochemical variables. 4. Adverse events.
Notes	1. Because a high incidence of side effects was noted in the first 39 patients, the last 13 patients were begun on a dose of 250 mg per day, which was gradually increased to 1g per day over a six‐week period. 2. Correspondence sent to the author on 2 December 2003. Reply was received on 19 December 2003. No additional information was added.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Neuberger 1985

Methods	Generation of allocation sequence: unclear. Allocation concealment: unclear. Blinding: inadequate. Follow‐up: adequate, 35 patients in the D‐penicillamine and seven patients in the placebo group were lost to follow‐up.
Participants	Country: UK, Spain, Denmark. Mean age: not reported. Female/Male: 173/16. PBC stage status: 12% patients in D‐penicillamine and 15% in placebo with stage 1; 40% in D‐penicillamine and 37% in placebo with stage 2; 24% in D‐penicillamine and 21% in placebo with stage 3; 24% in D‐penicillamine and 27% in placebo with stage 4. Inclusion criteria: 1. A clinical and histological picture compatible with that of primary biliary cirrhosis. 2. Raised alkaline phosphatase in the absence of evidence of extrahepatic biliary obstruction.
Interventions	D‐penicillamine 1.2 g/day, increased from 300 mg by 300 mg each fortnight until 1.2 g (n = 98) Placebo, taken in the same way (n = 91). Analysed duration of trial: 4 years.
Outcomes	1. Clinical features. 2. Liver biochemical variables. 3, Liver histology. 4. Survival data. 5. Adverse events.
Notes	1. It was an international multicentre (3 centres) trial. 2. Correspondence with the author 2 December 2003. Reply was received on 3 December 2003. No additional information was added.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Taal 1983

Methods	Generation of allocation sequence: unclear. Allocation concealment: unclear. Blinding: adequate, identical placebo. Follow‐up: adequate, 2 in the D‐penicillamine and 4 in the placebo group were lost to follow‐up.
Participants	Country: Netherlands. Median age: 51 years in D‐penicillamine, 48 years in placebo. Female/Male: 23/1. PBC stage status: not reported. Inclusion criteria: 1. Raised serum alkaline phosphatases. 2. AMA test positive. 3. A liver biopsy showing lymphoplasmacellular infiltrates with destruction of interlobular bile ducts or a paucity of bile ducts, and no demonstrable abnormalities of the extrahepatic bile ducts on the cholangiogram. 4. Only symptomatic patients (fatigue, pruritus, and/or jaundice).
Interventions	D‐penicillamine 1 g/day (increased from 250 mg every month until 1 g for the first 6 months. After that, decreased to 500 mg/day for the remaining 6 months (n = 11). Placebo taken in the same way (n = 13). Duration of treatment: 1 year Duration of post‐treatment follow‐up: 0.5 year. Analysed duration of trial: 1.5 years.
Outcomes	1. Survival data. 2. PBC‐related symptoms. 3. Liver biochemical variables. 4. Liver histological variables. 5. Adverse events.
Notes	1. It involved two centres. 2. Correspondence sent to the author on 2 December 2003. Reply was received on 3 December 2003. No additional information was added.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

PBC: primary biliary cirrhosis
AMA: antimitochondrial antibody

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Gupta 1982	An observational study, examing for three years the serum levels of immune complexes from 88 patient with primary biliary cirrhosis, treated with D‐penicillamine.
Savolainen 1983	Non‐randomised clinical study.
Triger 1980	Non‐randomised clinical study.

Data and analyses

Open in table viewer

Comparison 1. D‐penicillamine versus placebo/no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (expressed as relative risk) ‐ fixed effect model Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
Open in figure viewer Analysis 1.1 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 1 Mortality (expressed as relative risk) ‐ fixed effect model.
2 Mortality (expressed as relative risk) ‐ random effects model Show forest plot	6	628	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.85, 2.50]
Open in figure viewer Analysis 1.2 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 2 Mortality (expressed as relative risk) ‐ random effects model.
3 Subgroups of methodological quality ‐ generation of allocation sequence ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 3 Subgroups of methodological quality ‐ generation of allocation sequence ‐ mortality.
3.1 Adequate generation of allocation sequence	1	227	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.73, 1.38]
3.2 Unclear or inadequate generation of allocation sequence	5	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [1.23, 2.08]
4 Subgroups of methodological quality ‐ allocation concealment ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
Open in figure viewer Analysis 1.4 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 4 Subgroups of methodological quality ‐ allocation concealment ‐ mortality.
4.1 Adequate allocation concealment	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.94, 1.72]
4.2 Unclear or inadequate allocation concealment	4	349	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]
5 Subgroups of methodological quality ‐ blinding ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
Open in figure viewer Analysis 1.5 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 5 Subgroups of methodological quality ‐ blinding ‐ mortality.
5.1 Adequate blinding	4	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.83, 1.39]
5.2 Unclear or blinding not performed	2	227	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [1.38, 2.72]
6 Subgroups of methodological quality ‐ follow‐up ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
Open in figure viewer Analysis 1.6 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 6 Subgroups of methodological quality ‐ follow‐up ‐ mortality.
6.1 Adequate follow‐up	5	530	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.20, 1.87]
6.2 Unclear or inadequate follow‐up	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.17]
7 Subgroups of dosage ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 7 Subgroups of dosage ‐ mortality.
7.1 D‐penicillamine 1.2 g/day	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.19, 2.41]
7.2 D‐penicillamine 1 g/day	4	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.04, 1.84]
7.3 D‐penicillamine 0.6 g/day	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.17]
8 Subgroups of treatment and follow‐up duration ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
Open in figure viewer Analysis 1.8 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 8 Subgroups of treatment and follow‐up duration ‐ mortality.
8.1 Long‐term treatment and long‐term follow‐up	3	514	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.93, 1.43]
8.2 Short‐term treatment and short‐term follow‐up	3	114	Risk Ratio (M‐H, Fixed, 95% CI)	3.37 [1.70, 6.66]
9 Subgroups of PBC histological stage ‐ mortality Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.9 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 9 Subgroups of PBC histological stage ‐ mortality.
9.1 PBC stage III or IV	2	287	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.63, 1.15]
9.2 PBC stage I or II	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Sensitivity analyses ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.10 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 10 Sensitivity analyses ‐ mortality.
10.1 Available patient course analysis	6	525	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.82, 1.43]
10.2 Assuming poor outcome	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
10.3 Assuming good outcome	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.71, 1.26]
10.4 Extreme case favouring D‐penicillamine	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.51, 0.86]
10.5 Extreme case favouring control	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.51, 2.43]
11 Mortality or liver transplantation ‐ fixed effect model Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.09, 1.63]
Open in figure viewer Analysis 1.11 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 11 Mortality or liver transplantation ‐ fixed effect model.
12 Mortality or liver transplantation ‐ random effects model Show forest plot	6	628	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.85, 2.48]
Open in figure viewer Analysis 1.12 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 12 Mortality or liver transplantation ‐ random effects model.
13 Patients without improvement of pruritus Show forest plot	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.99]
Open in figure viewer Analysis 1.13 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 13 Patients without improvement of pruritus.
14 Patients without improvement of liver complications Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.14 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 14 Patients without improvement of liver complications.
14.1 Gastrointestinal bleeding	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.14, 1.49]
14.2 Ascites	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.34, 1.14]
14.3 Hepatic encephalopathy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Liver histology Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.15 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 15 Liver histology.
15.1 Progression of liver histological stage	3	149	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.58, 1.58]
15.2 Worsening of histological inflammatory activity	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.26, 0.94]
16 Bilirubin (µmol/L) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	49.0 [‐43.44, 141.44]
Open in figure viewer Analysis 1.16 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 16 Bilirubin (µmol/L).
17 Alkaline phosphatases (IU/L) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	‐62.50 [‐294.67, 169.67]
Open in figure viewer Analysis 1.17 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 17 Alkaline phosphatases (IU/L).
18 Aspartate aminotransferase (IU/L) Show forest plot	1	30	Mean Difference (IV, Fixed, 95% CI)	‐38.0 [‐79.82, 3.82]
Open in figure viewer Analysis 1.18 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 18 Aspartate aminotransferase (IU/L).
19 Alanine aminotransferase (IU/L) Show forest plot	1	22	Mean Difference (IV, Fixed, 95% CI)	‐45.0 [‐75.11, ‐14.89]
Open in figure viewer Analysis 1.19 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 19 Alanine aminotransferase (IU/L).
20 Albumin (g/dL) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐1.04, 0.04]
Open in figure viewer Analysis 1.20 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 20 Albumin (g/dL).
21 Adverse event ‐ fixed effect model Show forest plot	6	617	Risk Ratio (M‐H, Fixed, 95% CI)	3.08 [2.31, 4.11]
Open in figure viewer Analysis 1.21 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 21 Adverse event ‐ fixed effect model.
22 Adverse event ‐ random effects model Show forest plot	6	617	Risk Ratio (M‐H, Random, 95% CI)	3.98 [1.43, 11.04]
Open in figure viewer Analysis 1.22 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 22 Adverse event ‐ random effects model.
23 Adverse event ‐ excluding Taal 1983 trial Show forest plot	5	593	Risk Ratio (M‐H, Fixed, 95% CI)	3.69 [2.62, 5.19]
Open in figure viewer Analysis 1.23 Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 23 Adverse event ‐ excluding Taal 1983 trial.

Open in table viewer

Comparison 2. High‐dose D‐penicillamine versus low‐dose D‐penicillamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.06, 1.05]
Open in figure viewer Analysis 2.1 Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 1 Mortality.
2 Patients without improvement of liver histological progression Show forest plot	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.31, 1.29]
Open in figure viewer Analysis 2.2 Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 2 Patients without improvement of liver histological progression.
3 Adverse event Show forest plot	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.81, 4.89]
Open in figure viewer Analysis 2.3 Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 3 Adverse event.

Analysis 1.1

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 1 Mortality (expressed as relative risk) ‐ fixed effect model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 2 Mortality (expressed as relative risk) ‐ random effects model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 3 Subgroups of methodological quality ‐ generation of allocation sequence ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 4 Subgroups of methodological quality ‐ allocation concealment ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.5

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 5 Subgroups of methodological quality ‐ blinding ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 6 Subgroups of methodological quality ‐ follow‐up ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.7

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 7 Subgroups of dosage ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.8

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 8 Subgroups of treatment and follow‐up duration ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.9

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 9 Subgroups of PBC histological stage ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.10

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 10 Sensitivity analyses ‐ mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.11

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 11 Mortality or liver transplantation ‐ fixed effect model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.12

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 12 Mortality or liver transplantation ‐ random effects model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.13

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 13 Patients without improvement of pruritus.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.14

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 14 Patients without improvement of liver complications.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.15

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 15 Liver histology.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.16

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 16 Bilirubin (µmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.17

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 17 Alkaline phosphatases (IU/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.18

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 18 Aspartate aminotransferase (IU/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.19

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 19 Alanine aminotransferase (IU/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.20

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 20 Albumin (g/dL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.21

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 21 Adverse event ‐ fixed effect model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.22

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 22 Adverse event ‐ random effects model.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.23

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 23 Adverse event ‐ excluding Taal 1983 trial.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.1

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 1 Mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.2

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 2 Patients without improvement of liver histological progression.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 3 Adverse event.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Table 1. Adverse events in the included trials

Trials	D‐penicillamine	Control
Bassendine 1982	Proteinuria, rash, 'lupus' syndrome, myasthenia, thrombocytopenia.	None.
Dickson 1985	Hypersensitivity, cytopenia, arthralgias, linchen planus, loss of taste, proteinuria.	Cytopenia, arthralgias, linchen planus, dysgeusia, proteinuria.
Epstein 1981	Rashes, proteinuria, neutropenia.	None.
Matloff 1982	Goodpasture‐like syndrome, myasthenia, proteinuria, linchen planus, arthralgias, splenomegaly, rash, loss of taste, stomatitis.	Proteinuria.
Neuberger 1985	Rash, proteinuria, thrombocytopenia, arthralgia, gastrointestinal upset, leucopenia, asthma, pemphigoid, loss of taste, psychosis, palpitations, non‐compliance.	Proteinuria, gastrointestinal upset, headaches, non‐compliance, neurological complications.
Taal 1983	Exanthema, gastrointestinal upset, loss of taste.	Exanthema, gastrointestinal upset.
Bodenheimer 1985	In 750 mg/day (high‐dose) group: Fever, rash, arthralgia, loss of taste, mouth ulcers, nausea, haemolysis, thrombocytopenia, neutropenia, pulmonary fibrosis, albuminuria, neuropathy. In 250 mg/day (low‐dose) group: Fever, rash, arthralgia, loss of taste, mouth ulcers, thrombocytopenia, neutropenia, pulmonary fibrosis, albuminuria, neuropathy.

Table 1. Adverse events in the included trials

Ir a la tabla de la revisión

Comparison 1. D‐penicillamine versus placebo/no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (expressed as relative risk) ‐ fixed effect model Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]

2 Mortality (expressed as relative risk) ‐ random effects model Show forest plot	6	628	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.85, 2.50]

3 Subgroups of methodological quality ‐ generation of allocation sequence ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Adequate generation of allocation sequence	1	227	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.73, 1.38]
3.2 Unclear or inadequate generation of allocation sequence	5	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [1.23, 2.08]
4 Subgroups of methodological quality ‐ allocation concealment ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]

4.1 Adequate allocation concealment	2	279	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.94, 1.72]
4.2 Unclear or inadequate allocation concealment	4	349	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]
5 Subgroups of methodological quality ‐ blinding ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]

5.1 Adequate blinding	4	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.83, 1.39]
5.2 Unclear or blinding not performed	2	227	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [1.38, 2.72]
6 Subgroups of methodological quality ‐ follow‐up ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]

6.1 Adequate follow‐up	5	530	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.20, 1.87]
6.2 Unclear or inadequate follow‐up	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.17]
7 Subgroups of dosage ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 D‐penicillamine 1.2 g/day	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.19, 2.41]
7.2 D‐penicillamine 1 g/day	4	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.04, 1.84]
7.3 D‐penicillamine 0.6 g/day	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.17]
8 Subgroups of treatment and follow‐up duration ‐ mortality Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]

8.1 Long‐term treatment and long‐term follow‐up	3	514	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.93, 1.43]
8.2 Short‐term treatment and short‐term follow‐up	3	114	Risk Ratio (M‐H, Fixed, 95% CI)	3.37 [1.70, 6.66]
9 Subgroups of PBC histological stage ‐ mortality Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 PBC stage III or IV	2	287	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.63, 1.15]
9.2 PBC stage I or II	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Sensitivity analyses ‐ mortality Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Available patient course analysis	6	525	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.82, 1.43]
10.2 Assuming poor outcome	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.09, 1.64]
10.3 Assuming good outcome	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.71, 1.26]
10.4 Extreme case favouring D‐penicillamine	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.51, 0.86]
10.5 Extreme case favouring control	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.51, 2.43]
11 Mortality or liver transplantation ‐ fixed effect model Show forest plot	6	628	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.09, 1.63]

12 Mortality or liver transplantation ‐ random effects model Show forest plot	6	628	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.85, 2.48]

13 Patients without improvement of pruritus Show forest plot	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.99]

14 Patients without improvement of liver complications Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

14.1 Gastrointestinal bleeding	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.14, 1.49]
14.2 Ascites	1	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.34, 1.14]
14.3 Hepatic encephalopathy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Liver histology Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

15.1 Progression of liver histological stage	3	149	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.58, 1.58]
15.2 Worsening of histological inflammatory activity	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.26, 0.94]
16 Bilirubin (µmol/L) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	49.0 [‐43.44, 141.44]

17 Alkaline phosphatases (IU/L) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	‐62.50 [‐294.67, 169.67]

18 Aspartate aminotransferase (IU/L) Show forest plot	1	30	Mean Difference (IV, Fixed, 95% CI)	‐38.0 [‐79.82, 3.82]

19 Alanine aminotransferase (IU/L) Show forest plot	1	22	Mean Difference (IV, Fixed, 95% CI)	‐45.0 [‐75.11, ‐14.89]

20 Albumin (g/dL) Show forest plot	1	29	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐1.04, 0.04]

21 Adverse event ‐ fixed effect model Show forest plot	6	617	Risk Ratio (M‐H, Fixed, 95% CI)	3.08 [2.31, 4.11]

22 Adverse event ‐ random effects model Show forest plot	6	617	Risk Ratio (M‐H, Random, 95% CI)	3.98 [1.43, 11.04]

23 Adverse event ‐ excluding Taal 1983 trial Show forest plot	5	593	Risk Ratio (M‐H, Fixed, 95% CI)	3.69 [2.62, 5.19]

Comparison 1. D‐penicillamine versus placebo/no intervention

Ir a la tabla de la revisión

Comparison 2. High‐dose D‐penicillamine versus low‐dose D‐penicillamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.06, 1.05]

2 Patients without improvement of liver histological progression Show forest plot	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.31, 1.29]

3 Adverse event Show forest plot	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.81, 4.89]

Comparison 2. High‐dose D‐penicillamine versus low‐dose D‐penicillamine

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Referencias

Referencias de los estudios incluidos en esta revisión

Bassendine 1982 {published data only}

Bodenheimer 1985 {published data only}

Dickson 1985 {published data only}

Epstein 1981 {published data only}

Matloff 1982 {published data only}

Neuberger 1985 {published data only}

Taal 1983 {published data only}

Referencias de los estudios excluidos de esta revisión

Gupta 1982 {published data only}

Savolainen 1983 {published data only}

Triger 1980 {published data only}

Referencias adicionales

Alderson 2003

Altman 2003

Balasubramaniam 1990

Ballardini 1984

Begg 1994

Beswick 1985

Christensen 1985

Deeks 2001a

Deeks 2001b

Deeks 2002

Deiss 1971

DeMets 1987

DerSimonian 1986

Egger 1997

Epstein 1979

Epstein 1982

Fregeau 1989

Glasziou 2002

Gluud 1993

Gluud 2002

Goulis 1999

Heathcote 1976

Higgins 2002

Hollis 1999

Hoofnagle 1986

ICH‐GCP 1997

Invernizzi 1997

Ioannidis 2001

James 1981

Kaplan 1991

Kaplan 1994

Kaplan 1996

Kim 2000

Kjaergard 2001

Lacerda 1995

Lindor 1995

Lipsky 1980

Macaskill 2001

Mattalia 1998

Metcalf 1996

Mitchison 1992

Moher 1998

Nimni 1972

Nyberg 1989

Poupon 1996

Prince 2000

Prince 2002

Scheuer 1967

Schulz 1995

Sternlieb 1964

Turchany 1997

Van den Oord 1986

Verma 1999

Vuoristo 1995

Warnes 1987

Wiesner 1990

Yamada 1986

Referencias de otras versiones publicadas de esta revisión

Gong 2007

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

Copiar o descargar referencia