Abstract
Background
Primary sclerosing cholangitis is a cholestatic disease. D‐penicillamine is suggested as a treatment option due to its copper reducing and immunomodulatory potential.
Objectives
To evaluate the beneficial and harmful effects of D‐penicillamine for patients with primary sclerosing cholangitis.
Search methods
Eligible trials were identified through searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register (August 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2005), MEDLINE (1950 to August 2005), EMBASE (1980 to August 2005), Science Citation Index EXPANDED (1945 to August 2005), and reference lists of relevant articles. Authors of trials and pharmaceutical companies known to produce D‐penicillamine were also contacted.
Selection criteria
Randomised clinical trials comparing D‐penicillamine in any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Trials were included irrespective of publication status, year of publication, language, or blinding.
Data collection and analysis
Both authors selected the trials, extracted data, and evaluated the methodological quality of the trials with respect to the generation of allocation sequence, allocation concealment, blinding, and follow‐up. The results were reported by intention‐to‐treat analysis. The outcomes were presented as relative risk (RR) or weighted mean difference (WMD), both with 95% confidence intervals (CI).
Main results
One randomised trial was identified and included in the review. It was of low methodological quality. The trial compared D‐penicillamine versus placebo in 70 patients with primary sclerosing cholangitis. Compared with placebo, D‐penicillamine therapy had no significant effect on mortality (RR 1.14, 95% CI 0.49 to 2.64), liver transplantation (RR 1.11, 95% CI 0.39 to 3.17), hepatic histologic progression (RR 1.17, 95% CI 0.79 to 1.74), or cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). D‐penicillamine led to a significant improvement in the serum aspartate aminotransferase (WMD ‐23.00 U/L; 95% CI ‐30.66 to ‐15.34), but not in serum bilirubin level (WMD 0.40 mg/L; 95% CI ‐0.19 to 0.99) and serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI ‐37.89 to 125.89). There were significantly more adverse events in patients receiving D‐penicillamine (P = 0.013).
Authors' conclusions
There is not sufficient evidence to support or refute the use of D‐penicillamine for patients with primary sclerosing cholangitis. We do not recommend the use of D‐penicillamine for patients with primary sclerosing cholangitis outside randomised trials.
Plain language summary
There is insufficient evidence to support or refute D‐penicillamine for patients with primary sclerosing cholangitis
D‐penicillamine has been considered for patients with primary sclerosing cholangitis due to its copper reducing and immunomodulatory potential. The only identified randomised clinical trial did not demonstrate any beneficial effect of D‐penicillamine on the course, complications, and survival of patients with primary sclerosing cholangitis. In addition, its use was associated with a number of adverse events. Therefore, we cannot recommend the use of D‐penicillamine outside randomised trials.
Background
Primary sclerosing cholangitis is a cholestatic disease of unknown etiology (Wiesner 1980; Angulo 1999; LaRusso 1999; Lazaridis 1999). Initially the disease was perceived by clinicians as rare. However, due to the increasing use of endoscopic retrograde cholangio‐pancreatography, primary sclerosing cholangitis is being increasingly diagnosed and currently is one of the most common indications for liver transplantation (Angulo 1999; LaRusso 1999; Alba 2002).
Primary sclerosing cholangitis is characterized by diffuse inflammation and fibrosis of the intra‐ and extrahepatic bile ducts. It generally follows a slowly progressive course and may lead to biliary cirrhosis, portal hypertension, and death from hepatic failure (Wiesner 1980; Lazaridis 1999). Some patients remain asymptomatic, whereas others present with jaundice, pruritus, non‐specific abdominal pain, fatigue, fever, or weight loss. In addition, the disease is commonly associated with inflammatory bowel disease, usually chronic ulcerative colitis (Wiesner 1980; Chapman 1984; LaRusso 1999; Lazaridis 1999; Meier 2001). Bacterial toxins, viral infections, and genetic and/or immunologic factors may contribute to the pathogenesis and progression of primary sclerosing cholangitis.
Currently, no therapy achieves a complete clinical, biochemical, or histological remission of primary sclerosing cholangitis. Nevertheless, therapeutic approaches include mechanical, surgical, and medical interventions. Until now there is no clinical evidence backing the introduction of mechanical or surgical methods for treatment of primary sclerosing cholangitis (LaRusso 1999; Lazaridis 1999). Medical approaches include corticosteroids, colchicine, bile acids, and D‐penicillamine (LaRusso 1999; Lazaridis 1999; Meier 2001). Colchicine has been tested in a randomised trial; however, without a beneficial effect (Olsson 1995). The evidence for treating primary sclerosing cholangitis with glucocorticosteroids and the beneficial and harmful effects of bile acids in patients with primary sclerosing cholangitis has been evaluated in two systematic Cochrane reviews (Chen 2003; Chen 2004). There was insufficient evidence either to support or refute beneficial effects of glucocorticosteroids for patients with primary sclerosing cholangitis (Chen 2004). Bile acids were found to improve liver biochemistry, but there was not sufficient evidence to either support or refute their effects on clinical outcomes (Chen 2003). In both cases, there is a need for large randomised clinical trials of high methodological quality (Chen 2003; Chen 2004).
Patients with primary sclerosing cholangitis are found to have abnormal copper metabolism (Wiesner 1980; Gross 1985). Hepatic copper accumulates and urinary excretion of copper increases with the progress of the disease (Wiesner 1980; Gross 1985; LaRusso 1999). The reason for this may be deterioration of hepatocyte function (Gross 1985). D‐penicillamine is a heavy metal chelating agent with antifibrogenic and immunosuppressive actions (Ludwig 1990). It has a mercapto group (‐SH) capable of binding a copper‐ion forming a soluble complex excreted in the urine, thereby decreasing the toxic levels of the metal (Sherlock 1975). Previous studies on D‐penicillamine have shown improvement of primary biliary cirrhosis, another chronic cholestatic disease with many similarities to primary sclerosing cholangitis. Therefore, a randomised trial of D‐penicillamine for treatment of patients with primary sclerosing cholangitis was initiated (LaRusso 1986a; LaRusso 1988a). However, no beneficial effect on disease progression was observed, and the drug was found to have considerable toxicity (LaRusso 1986a; LaRusso 1988a; LaRusso 1999). Until now we have been unable to find meta‐analyses or systematic reviews on D‐penicillamine for primary sclerosing cholangitis.
Objectives
To evaluate the beneficial and harmful effects of D‐penicillamine in patients with primary sclerosing cholangitis based on randomised clinical trials.
Methods
Criteria for considering studies for this review
Types of studies
All randomised clinical trials, regardless of publication status, year of publication, language, or blinding.
Types of participants
Patients with primary sclerosing cholangitis diagnosed on the basis of the following criteria: (1) Hepatic histological criteria, including cholangitis or portal hepatitis (stage 1); periportal fibrosis with periportal hepatitis (stage 2); septal fibrosis, necrosis, or both (stage 3); or biliary cirrhosis (stage 4). (2) Radiological criteria, including cholangiographic demonstration of diffusely distributed, short and annular strictures with intervening segments of normal or slightly dilated ducts; short band‐like strictures and diverticulum‐like outpouchings of the biliary tree. (3) Biochemical criteria, including elevated activity of serum alkaline phosphatases, serum transaminases (alanine aminotransferase or aspartate aminotransferase), and/or increase in total serum bilirubin.
Types of interventions
D‐penicillamine in any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Co‐interventions were allowed if used in both intervention arms.
Types of outcome measures
Primary outcome measures:
All‐cause mortality.
Morbidity related to the liver (liver transplantation, biliary cirrhosis, bile duct cancer, and signs of hepatic decompensation such as ascites, bleeding varices, and/or splenomegaly).
Secondary outcome measures:
Histological response (number of patients with histological deterioration).
Radiological response (number of patients with radiological deterioration).
Biochemical responses (serum activities of alkaline phosphatases, aspartate aminotransferase, and serum bilirubin concentration, and/or number of patients with abnormal values of alkaline phosphatases, aspartate aminotransferase, and/or serum bilirubin).
Clinical findings (eg, pruritus and fatigue).
Adverse events (defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment, but did, however, result in a dose reduction or discontinuation of treatment. A serious adverse event was defined according to the ICH guidelines (ICH‐GCP 1997) as any event that led to death, was life‐threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or congenital anomaly/birth defect, or any important medical event, which might have jeopardized the patient or required intervention to prevent it).
Search methods for identification of studies
We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register (August 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2005), MEDLINE (1950 to August 2005), EMBASE (1980 to August 2005) and Science Citation Index EXPANDED (1945 to August 2005). We applied the search strategies as described in Table 1 (see 'Additional tables').
1. Search strategies.
| Database | Time span | Search strategy |
| Cochrane Hepato‐Biliary Group Controlled Trials Register | August 2005 | cholangitis AND penicillamine |
| The Cochrane Central Register of Controlled Trials on The Cochrane Library | Issue 3, 2005 | #1 CHOLANGITIS explode all trees (MeSH) #2 cholangitis #3 (#1 or #2) #4 PENICILLAMINE explode all trees (MeSH) #5 penicillamine #6 (#4 or #5) #7 (#3 and #6) |
| MEDLINE | 1950 to August 2005 | #1 explode "Cholangitis"/ all subheadings #2 cholangitis #3 #1 or #2 #4 explode "Penicillamine"/ all subheadings #5 penicillamine #6 #4 or #5 #7 #3 and #6 #8 random* or blind* or placebo or meta‐analysis #9 #7 and #8 |
| EMBASE | 1980 to August 2005 | #1 explode "cholangitis"/ all subheadings #2 cholangitis #3 #1 or #2 #4 explode "penicillamine"/ all subheadings #5 penicillamine #6 #4 or #5 #7 #3 and #6 #8 random* or blind* or placebo or meta‐analysis #9 #7 and #8 |
| Science Citation Index EXPANDED | 1945 to August 2005 | #1 TS=cholangitis #2 TS=penicillamine #3 #2 AND #1 #4 TS=(random* OR blind* OR placebo* OR meta‐analysis) #5 #4 AND #3 |
Further trials were sought through scanning of reference lists of relevant articles. In addition, the principal author of the included randomised clinical trial and pharmaceutical companies producing D‐penicillamine were contacted for information on additional published or unpublished randomised clinical trials.
Data collection and analysis
Trial selection Identified trials were listed, and each contributor independently evaluated which trials fulfilled the inclusion criteria. Excluded trials were listed with the reason for exclusion. Disagreements were resolved by discussion. Data extraction Both authors extracted the following data from the included trials and disagreements were resolved by discussion:
Primary author.
Trial characteristics: date, location and funding of the trial, length of follow‐up, use of intention‐to‐treat analyses, as well as the publication status.
Patient characteristics: number of patients randomised, inclusion and exclusion criteria, mean (or median) age, sex ratio, proportion of intra‐ and extrahepatic primary sclerosing cholangitis, and presence of inflammatory bowel disease.
Intervention characteristics: dose, duration, and mode of administration of D‐penicillamine and/or of additional intervention(s).
Outcome measures: number of events in the intervention group and in the control group (including the number and type of adverse events).
Assessment of methodological quality We defined the methodological quality as the confidence that the design and report restricted bias in the intervention comparison (Moher 1998; Kjaergard 2001). Due to the risk of overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001), we assessed the influence of methodological quality.
Generation of the allocation sequence
Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and was excluded from the present review when assessing beneficial effects.
Allocation concealment
Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes.
Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Blinding (or masking)
Adequate, if the trial was described as double blind and the method of blinding involved identical placebo or active drugs.
Unclear, if the trial was described as double blind, but the method of blinding was not described.
Not performed, if the trial was not double blind.
Follow‐up
Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
Inadequate, if the number or reasons for dropouts and withdrawals were not described.
Furthermore, we registered whether or not the randomised clinical trials used 'intention‐to‐treat' analysis (Gluud 2001) and sample size calculation.
Since data were not reported sufficiently in the one identified trial we contacted the authors to retrieve missing data. No answer was received.
Statistical methods We performed the analyses in RevMan Analyses 1.0 (RevMan 4.2) according to the intention‐to‐treat method using the last reported observed response ('carry forward') for continuous outcomes and including all randomised patients irrespective of compliance or follow‐up whenever possible. Regarding death, both a worst‐case scenario analysis considering all dropped‐out patients as dead and a best‐case scenario analysis considering all dropped‐out patients alive was planned to be carried out. We performed per‐protocol analyses in the assessment of the histological response. Data were analysed by both fixed‐effect (DeMets 1987) and random‐effects model (DerSimonian 1986). Since there were no significant differences between the two methods, only the results of the fixed‐effect model was reported. The presence of publication bias and other biases was planned to be assessed by funnel plots (Egger 1997). We expressed binary outcome measures as relative risks (RR) and continuous data as weighted mean difference (WMD), both with 95% confidence intervals.
Subgroup/sensitivity analyses We planned the following subgroup/sensitivity analyses:
Methodological quality of the randomised clinical trial ‐ comparing adequately with inadequately or unclearly performed trials.
Dose and duration of treatment with D‐penicillamine ‐ comparing trials with D‐penicillamine intervention at or above the median dose or duration given with trials administrating less doses or shorter duration.
Trials with or without co‐interventions.
Extension of primary sclerosing cholangitis ‐ intra‐ versus extrahepatic primary sclerosing cholangitis.
Publication status ‐ comparing full manuscript trials with all other identified trials (abstracts, unpublished studies or similar).
Results
Description of studies
We identified 33 references through the electronic searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 4), The Cochrane Central Register of Controlled Trials in The Cochrane Library (n = 5), MEDLINE (n = 5), EMBASE (n = 16) and Science Citation Index EXPANDED (n=3). Of these references, we excluded 30 duplicates, reviews, and clearly irrelevant references. Accordingly, three references were retrieved. Through manual searches of reference lists, correspondence with authors, and correspondence with pharmaceutical companies producing D‐penicillamine (Eli Lilly, Swedish Orphan and Biomedic Laboratories) no additional references were identified.
Of the three retrieved publications, two fulfilled the inclusion criteria of the present review (LaRusso 1986a; LaRusso 1988b). The two studies described one randomised clinical trial. One of the references (LaRusso 1986a) was only published as an abstract. The third study was excluded because it did not describe a randomised study, but just followed the patients from the study by LaRusso et al (included study) for estimating the prevalence of cholangiocarcinoma associated with primary sclerosing cholangitis (Rosen 1991).
The study by LaRusso et al was published in 1988 and evaluated the therapeutic efficacy of D‐penicillamine in patients with primary sclerosing cholangitis.
Patients The sample size of the trial was 70 patients. The mean age of the patients was 42 years (range 17 to 71), and 63% of the patients were male. Inflammatory bowel disease (chronic ulcerative colitis) was diagnosed in 66% of the patients. The patients were stratified based on the presence or absence of cirrhosis or varices.
Interventions The patients were randomly assigned to D‐penicillamine (n = 39) or identical looking placebo capsules (n = 31). The randomisation was weighted in favour of the drug in anticipation of possible drug toxicity requiring severance from the study. The two treatment groups were comparable at the time of randomisation with regard to clinical, biochemical, cholangiographic, and hepatic histologic indices. The initial dose was one capsule per day (250 mg D‐penicillamine) for four weeks. The dose was increased by one capsule per day every four weeks until a maintenance dose of three capsules per day was achieved. Patients were re‐examined 6 months and 1 year after entry and at yearly intervals thereafter. Liver biopsies and endoscopic retrograde cholangiograms were repeated at 12 months intervals or as clinically indicated.
Follow‐up Adverse events led to permanent discontinuation of D‐penicillamine in eight patients (two had allergic reactions, one had cytopenia, and five had proteinuria). Minor reactions were observed in 29 patients (20 in the D‐penicillamine group and nine in the placebo group).
Outcome measures The outcome measures were overall survival; time to treatment failure (failure based on clinical, biochemical, cholangiographic, and hepatic histologic indices); changes in biochemical variables after one year; progression of hepatic histology; overall progression of clinical, biochemical, and hepatic histological variables.
The reasons for inclusion and exclusion of the identified trials are listed under 'Characteristics of included studies' and 'Characteristics of excluded studies', respectively.
Risk of bias in included studies
The trial was randomised, but the generation of the allocation sequence was not described and allocation concealment was not reported. Blinding was adequate using an identical appearing placebo. Follow‐up of the patients was inadequately described. Accordingly, the trial was of low methodological quality.
Sample size calculation was not reported and intention‐to‐treat analysis was neither stated or used. D‐penicillamine and placebo were sponsored by a pharmaceutical company.
Effects of interventions
The trial included in this review recruited 70 patients. Median follow‐up was 3.9 years for patients still alive and 1.2 years for patients who died (LaRusso 1988b).
All cause mortality No significant effect of D‐penicillamine versus placebo could be demonstrated on mortality (RR 1.14, 95% CI 0.49 to 2.64). In the D‐penicillamine group, 10/39 (25.6%) patients died versus 7/31 (22.6%) patients in the placebo group (Comparison 01‐01). The reasons for the deaths were not reported, but no patients died because of D‐penicillamine.
Liver transplantation Treatment with D‐penicillamine could not significantly decrease the risk of liver transplantation compared to placebo (RR 1.11, 95% CI 0.39 to 3.17). In the D‐penicillamine group, 7/39 (17.9%) patients received liver transplantation versus 5/31 (16.1%) patients in the placebo group (Comparison 01‐02).
Hepatic histologic progression Histologic progression was defined as an increase of one stage or more on liver biopsy specimens (see 'Types of participants' for criteria). D‐penicillamine did not significantly decrease the number of patients developing abnormalities on liver biopsy (RR 1.17, 95% CI 0.79 to 1.74). In the D‐penicillamine group, 25/39 (64.1%) patients increased at least one stage versus 17/31 (54.8%) patients in the placebo group (Comparison 01‐03).
Cholangiographic deterioration D‐penicillamine was not found to significantly decrease the risk of cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). In the D‐penicillamine group, 11/39 (28.2%) patients showed deterioration in the form of increasing stricture formation or increasing irregularities of the mucosal surfaces of the ducts versus 10/31 (32.3%) patients in the placebo group (Comparison 01‐04).
Biochemical changes D‐penicillamine had no significant effect on the serum bilirubin concentration (WMD 0.40 mg/L; 95% CI ‐0.19 to 0.99) (Comparison 01‐05) or on the serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI ‐37.89 to 125.89) (Comparison 01‐6). D‐penicillamine led, however, to a significant decrease in serum aspartate aminotransferase activity (WMD ‐23.00 U/L; 95% CI ‐30.66 to ‐15.34) (Comparison 01‐07). Clinical findings We did not find any data on clinical findings in the included trial. However, the authors stated that there was no consistent clinical improvement in either the D‐penicillamine or the placebo group with regard to symptoms such as pruritus or fatigue (LaRusso 1988b).
Adverse events According to the trial report, D‐penicillamine (750 mg per day) was not found to have any beneficial effect on the course, complications, and survival of patients with primary sclerosing cholangitis within 36 months, and its use was associated with a number of adverse events leading to permanent discontinuation of therapy (allergic reactions, cytopenia and proteinuria).
Calculating the relative risk (RR), there was a non‐significant trend towards D‐penicillamine causing more adverse events compared to placebo (RR 13.60, 95% CI 0.82 to 226.81) (Comparison 01‐8). In the D‐penicillamine group, 8/39 (20.5%) patients experienced adverse events (see above) versus none in the placebo group (0/31 patients, 0%). However, since one of the cells in the 2 x 2 table is zero the method is very approximate and the odds ratio is infinite. We therefore used Fisher's exact probability test, which is more appropriate in this case. With this test the two‐tailed value equals P = 0.013 and hence the harmful effect of D‐penicillamine is statistically significant.
Discussion
Only one trial was included in this systematic review. It was of low methodological quality and had a small sample size. This is clearly not enough evidence to draw any conclusion about the effect of D‐penicillamine in the treatment of primary sclerosing cholangitis.
The study by LaRusso et al found that D‐penicillamine had no significant beneficial effect on the mortality in patients with primary sclerosing cholangitis, on the course of the disease, or on complications related to it (LaRusso 1988b). In addition, according to Fisher's exact probability test the use of D‐penicillamine was associated with a significant incidence of adverse events (allergic reactions, cytopenia, and proteinuria) requiring permanent discontinuation of the drug. Marginal beneficial effects and clear adverse events have been observed in several other studies using D‐penicillamine for treating, among others, Wilson's disease (Pandit 2002; Subramanian 2002), rheumatoid arthritis (Suarez‐Almazor 2000), primary biliary cirrhosis (Bodenheimer 1985; Dickson 1985), and Sjögren's syndrome (ter Borg 2002). However, small trials may carry a considerable risk of type II errors, ie, they fail to demonstrate a difference when it is actually present (Pocock 1983; Altman 1999). No sample size calculation was performed in the study by LaRusso et al (LaRusso 1988b). A significant beneficial effect of D‐penicillamine might therefore have been observed if more patients were entered into the trial. However, in that case there would also be a risk of a corresponding higher number of adverse events. In addition, a systematic review on D‐penicillamine for primary biliary cirrhosis (Gong 2004) showed that D‐penicillamine was found to increase mortality. Therefore, the use of D‐penicillamine for patients with primary sclerosing cholangitis seems less attractive. We are, however, not able to exclude that D‐penicillamine may work, potentially at a lower dosage (Gong 2004).
Without large, well‐conducted, randomised clinical trials, we cannot recommend the use of D‐penicillamine for treating primary sclerosing cholangitis. However, the absence of beneficial effect in the one clinical trial found, its high rate of adverse events, and taking into account the high costs of conducting clinical trials, seem to discourage the performance of additional clinical trials of D‐penicillamine for this disease. Actually, research efforts may be better spent on more promising treatments. Several medical treatments with different mechanisms of action, including immunosuppressants, anti‐inflammatory agents, antifibrotic drugs, and bile acids have been investigated alone or in combination, but none have shown convincing evidence of benefit and currently, no medical therapy, aiming at disrupting disease progression, is available. So far, liver transplantation is the only therapeutic alternative that improves survival in patients with end‐stage primary sclerosing cholangitis (Alba 2002; Broome 2002a; Broome 2002b; Cullen 2005). Despite the lack of beneficial effect and the high incidence of adverse events associated with the use of D‐penicillamine for primary sclerosing cholangitis in the study by LaRusso et al, the trial generated important and, at that time, novel data on clinical, biochemical, radiologic, and histologic features of the disease. Understanding the pathogenic process of the disease is important in order to find an effective medical treatment for patients with primary sclerosing cholangitis.
Authors' conclusions
Implications for practice.
We do not recommend D‐penicillamine for patients with primary sclerosing cholangitis because of the insufficient evidence that exists.
Implications for research.
Future randomised trials on D‐penicillamine may be considered, preferably using lower dosages, and should involve strict monitoring through the establishment of an Independent Data Monitoring and Safety Committee. Any future trial should adopt the CONSORT statement for reporting (www.consort‐statement.org).
What's new
| Date | Event | Description |
|---|---|---|
| 22 September 2008 | Amended | Converted to new review format. |
Acknowledgements
The authors would like to acknowledge Dimitrinka Nikolova and Nader Salas for expert assistance during the preparation of this systematic review. We also thank the peer‐reviewers and the contact editors for helpful comments.
Data and analyses
Comparison 1. D‐penicillamine versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Mortality | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.49, 2.64] |
| 2 Liver transplantation | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.39, 3.17] |
| 3 Hepatic histologic progression | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.79, 1.74] |
| 4 Cholangiographic deterioration | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.43, 1.79] |
| 5 Bilirubin (mg/dl) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐0.19, 0.99] |
| 6 Alkaline phosphatases (U/L) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 44.0 [‐37.89, 125.89] |
| 7 Aspartate aminotransferase (U/L) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐23.0 [‐30.66, ‐15.34] |
| 8 Adverse events | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 13.6 [0.82, 226.81] |
1.1. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 1 Mortality.
1.2. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 2 Liver transplantation.
1.3. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 3 Hepatic histologic progression.
1.4. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 4 Cholangiographic deterioration.
1.5. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 5 Bilirubin (mg/dl).
1.6. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 6 Alkaline phosphatases (U/L).
1.7. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 7 Aspartate aminotransferase (U/L).
1.8. Analysis.
Comparison 1 D‐penicillamine versus placebo, Outcome 8 Adverse events.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
LaRusso 1988b.
| Methods | Generation of allocation sequence: Unclear (not reported). Allocation concealment: Unclear (not described). Patients were stratified based on the presence or absence of cirrhosis on liver biopsy or varices on radiographic or endoscopic examination of the upper gastrointestinal tract. Double blinding: Yes (identical looking capsules). Follow‐up: Inadequate (Number and reasons of dropouts in the placebo group not described.). Sample size calculation: Not performed. Intention‐to‐treat analysis: Not stated and not used. |
|
| Participants | Inclusion criteria: Diagnosis of primary sclerosing cholangitis based on: established liver disease of more than six months duration; a serum activity of alkaline phosphatases more than twice the upper limit of normal; a cholangiogram demonstrating diffuse narrowing, irregularity, dilation, and tortuosity of the extrahepatic biliary ductal system with or without involvement of the intrahepatic ductal system; and a pre‐entry liver biopsy specimen compatible with the diagnosis of primary sclerosing cholangitis. Exclusion criteria: Previous biliary tract surgery or documented choledocholithiasis before the diagnosis of primary sclerosing cholangitis; radiographic changes strongly suggestive of cholangiocarcinoma; alcohol abuse; or a malignancy other than skin cancer. Characteristics of included patients: Mean age: 42 years. Proportion of males: 63%. Proportion of intra‐ and extrahepatic primary sclerosing cholangitis: not reported. Presence of inflammatory bowel disease (chronic ulcerative colitis): 66%. |
|
| Interventions | Initial dose: one capsule of penicillamine (250 mg) or placebo each day for four weeks. The dose was increased by one capsule per day every four weeks until a maintenance dose of three capsules per day was reached. Patients were reexamined six months and one year after entry and at yearly intervals thereafter. Liver biopsies and endoscopic retrograde cholangiograms were repeated at 12 months intervals or as clinically indicated. |
|
| Outcomes | Mortality. Morbidity related to the liver (liver transplantation). Hepatic histological progression. Cholangiographic deterioration. Changes in biochemical values (eg, bilirubin, alkaline phosphatase, and aspartate aminotransferase). Adverse events. | |
| Notes | Country: USA
Language: English
Funding: penicillamine and placebo furnished by a pharmaceutical company. Letter sent to authors in April 2003. No reply received. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Rosen 1991 | Not a randomised trial. The study estimates the prevalence of cholangiocarcinoma associated with primary sclerosing cholangitis by following the patients from the included study (LaRusso et al, 1988b). |
Contributions of authors
SLK drafted the protocol and the review, developed the search strategies, and performed the statistical analyses. Both authors selected the trials and performed the data extractions. WDC also participated in the revision of the protocol and review.
Sources of support
Internal sources
Copenhagen Trial Unit, Denmark.
External sources
Copenhagen Hospital Corporation Research Foundation, Denmark.
Declarations of interest
None known.
Edited (no change to conclusions)
References
References to studies included in this review
LaRusso 1988b {published data only}
- LaRusso N, Wiesner R, Ludwig J, MacCarty R, Beaver S, Zinsmeister A, et al. Randomized trial of penicillamine in primary sclerosing cholangitis. Hepatology 1986;6(5):1205. [DOI] [PubMed] [Google Scholar]
- LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 1988;95(4):1036‐42. [MEDLINE: ] [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Rosen 1991 {published data only}
- Rosen CB, Nagorney DM, Wiesner RH, Coffey RJ, LaRusso NF. Cholangiocarcinoma complicating primary sclerosing cholangitis. Annals of Surgery 1991;213(1):21‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Additional references
Alba 2002
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