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Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 1 Mortality (expressed as relative risk) ‐ fixed effect model.
Figures and Tables -
Analysis 1.1

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 2 Mortality (expressed as relative risk) ‐ random effects model.
Figures and Tables -
Analysis 1.2

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 3 Subgroups of methodological quality ‐ generation of allocation sequence ‐ mortality.
Figures and Tables -
Analysis 1.3

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 4 Subgroups of methodological quality ‐ allocation concealment ‐ mortality.
Figures and Tables -
Analysis 1.4

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 5 Subgroups of methodological quality ‐ blinding ‐ mortality.
Figures and Tables -
Analysis 1.5

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 6 Subgroups of methodological quality ‐ follow‐up ‐ mortality.
Figures and Tables -
Analysis 1.6

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 7 Subgroups of dosage ‐ mortality.
Figures and Tables -
Analysis 1.7

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 8 Subgroups of treatment and follow‐up duration ‐ mortality.
Figures and Tables -
Analysis 1.8

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 9 Subgroups of PBC histological stage ‐ mortality.
Figures and Tables -
Analysis 1.9

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 10 Sensitivity analyses ‐ mortality.
Figures and Tables -
Analysis 1.10

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 11 Mortality or liver transplantation ‐ fixed effect model.
Figures and Tables -
Analysis 1.11

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 12 Mortality or liver transplantation ‐ random effects model.
Figures and Tables -
Analysis 1.12

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 13 Patients without improvement of pruritus.
Figures and Tables -
Analysis 1.13

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 14 Patients without improvement of liver complications.
Figures and Tables -
Analysis 1.14

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 15 Liver histology.
Figures and Tables -
Analysis 1.15

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 16 Bilirubin (µmol/L).
Figures and Tables -
Analysis 1.16

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 17 Alkaline phosphatases (IU/L).
Figures and Tables -
Analysis 1.17

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 18 Aspartate aminotransferase (IU/L).
Figures and Tables -
Analysis 1.18

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 19 Alanine aminotransferase (IU/L).
Figures and Tables -
Analysis 1.19

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 20 Albumin (g/dL).
Figures and Tables -
Analysis 1.20

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 21 Adverse event ‐ fixed effect model.
Figures and Tables -
Analysis 1.21

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 22 Adverse event ‐ random effects model.
Figures and Tables -
Analysis 1.22

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

Comparison 1 D‐penicillamine versus placebo/no intervention, Outcome 23 Adverse event ‐ excluding Taal 1983 trial.
Figures and Tables -
Analysis 1.23

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

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 1 Mortality.
Figures and Tables -
Analysis 2.1

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

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 2 Patients without improvement of liver histological progression.
Figures and Tables -
Analysis 2.2

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

Comparison 2 High‐dose D‐penicillamine versus low‐dose D‐penicillamine, Outcome 3 Adverse event.
Figures and Tables -
Analysis 2.3

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

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.

Figures and Tables -
Table 1. Adverse events in the included trials
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]

Figures and Tables -
Comparison 1. D‐penicillamine versus placebo/no intervention
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]

Figures and Tables -
Comparison 2. High‐dose D‐penicillamine versus low‐dose D‐penicillamine