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16025FW: NATAP: Milk Thistle Study Found No Benefit

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  • alleypat
    Dec 28, 2005
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      Milk Thistle for Alcoholic and/or Hepatitis B or C Liver Diseases: study
      showed no benefit-A Systematic Cochrane Hepato-Biliary Group Review with
      Meta-Analyses of Randomized Clinical Trials

      The American Journal of Gastroenterology
      Volume 100 Page 2583 - November 2005

      Andrea Rambaldi, M.D.1, Bradly P. Jacobs, M.D., M.P.H.2, Gaetano Iaquinto,
      M.D.3, and Christian Gluud, M.D., Dr. Med. Sci.1

      ABSTRACT
      OBJECTIVES: Our objectives were to assess the beneficial and harmful effects
      of milk thistle (MT) or MT constituents versus placebo or no intervention in
      patients with alcoholic liver disease and/or hepatitis B and/or C liver
      diseases.

      METHODS: Randomized clinical trials studying patients with alcoholic and/or
      hepatitis B or C liver diseases were included (December 2003). The
      randomized clinical trials were evaluated by components of methodological
      quality.

      RESULTS: Thirteen randomized clinical trials assessed MT in 915 patients
      with alcoholic and/or hepatitis B or C liver diseases. The methodological
      quality was low: only 23% of the trials reported adequate allocation
      concealment and only 46% were considered double blind. MT versus placebo or
      no intervention for a median duration of 6 months had no significant effects
      on all-cause mortality (relative risk (RR) 0.78, 95% confidence interval
      (CI) 0.53-1.15), complications of liver disease, or liver histology.
      Liver-related mortality was significantly reduced by MT in all trials (RR
      0.50, 95% CI 0.29-0.88), but not in high-quality trials (RR 0.57, 95% CI
      0.28-1.19). MT was not associated with a significantly increased risk of
      adverse events.

      CONCLUSIONS: Based on high-quality trials, MT does not seem to significantly
      influence the course of patients with alcoholic and/or hepatitis B or C
      liver diseases. MT could potentially affect liver injury. Adequately
      conducted randomized clinical trials on MT versus placebo may be needed.

      INTRODUCTION
      Extracts of milk thistle (MT), Silybum marianum (L) Gaertneri, have been
      used as medical remedies since the time of ancient Greece and are widely
      used as an alternative medication (1-3). Silymarin is the collective name
      for the flavonolignans (silybin or silibinin, silydianin, silychristin)
      extracted from the MT (2). These extracts have been shown to protect animals
      against various hepatotoxins including acetaminophen (4, 5), radiation (6),
      iron overload (7), phaloidin (8, 9), carbon tetrachloride (10-12), and
      thioacetamide (13). The "hepatoprotective" actions of MT may include
      inhibition of lipid peroxide formation, scavenging of free radicals, and
      changing of the physical properties of cell membranes (1, 14-16). Increased
      lipid peroxidation is frequent in all stages of liver damage from alcoholic
      and non-alcoholic liver disease (17). MT may also reduce liver fibrogenesis
      (18, 19).

      This systematic review summarizes the data from randomized clinical trials
      to examine the beneficial and harmful effects of MT for alcoholic and/or
      hepatitis B or C liver diseases. The reasons for focusing on these
      disorders, having different etiologies, are the following. First, many
      trials conducted before the 1980s did not exclude the etiology of hepatitis
      B virus and many trials conducted before the 1990s did not exclude the
      etiology of hepatitis C virus. Second, alcoholic and viral liver diseases
      often coexist. Third, alcohol and hepatitis B and/or C constitute the major
      etiologies of chronic liver diseases in the Western World (20).

      DISCUSSION

      We found no significant effect of MT on all-cause mortality. We observed a
      potential beneficial effect of MT on mortality in patients with alcoholic
      liver disease, but this effect could not be confirmed in two high-quality
      trials. We also observed a potential beneficial effect of MT on
      liver-related mortality, but again this effect could not be demonstrated in
      three high-quality trials. As the methodological quality of some of the
      trials was low, we are not able to exclude bias as the cause of our positive
      findings (24-26). The methods and definitions used to establish
      liver-related mortality varied or were unclear. Therefore, this outcome
      measure should be cautiously evaluated. Further, publication bias and
      selective reporting bias must be considered (56, 57). The estimate on
      all-cause mortality in high-quality trials was a RR of 0.95 (95% CI
      0.55-1.65). This estimate is compatible with a 45% reduction in all-cause
      mortality as well as with a 65% increase in all-cause mortality. In general,
      one should only introduce interventions based on findings in high-quality
      trials (24-26).

      Our observations confirm two recent meta-analyses on MT for patients with
      liver disease of any cause (3, 58, 59), in spite of the following facts. Our
      systematic review included five more randomized clinical trials (41, 44, 52,
      54, 55), excluded data from quasi-randomized clinical trials (59), which may
      significantly bias estimates of interventions effects (26, 60), and included
      more patients with alcoholic liver disease (3).

      The statistically significant effect of MT on all-cause mortality identified
      in subgroup analysis of patients with alcohol-related liver disease were not
      confirmed in a further subgroup analysis including patients with alcoholic
      liver disease co-infected by HCV. Further, this effect could not be
      demonstrated in three high-quality trials (24-26). Therefore our findings
      are not robust enough to form a fundament for therapeutic recommendations.

      We found that MT significantly improved two liver biochemical variables,
      s-bilirubin and GGT. For the remainder of our analyses on liver biochemistry
      markers, MT had either effects that were dependent on the statistical model
      we used or had no significant effects. Further, when focusing on
      high-quality trials we could not demonstrate significant effects (24-26). In
      all circumstances the effects of MT on liver biochemistry were not dramatic.

      This systematic review has a number of potential limitations. First, the
      small sample size limits the power of our meta-analyses. The CI for the
      pooled estimate is sufficiently wide, meaning that a substantial benefit or
      harm cannot be excluded. Our review does not preclude the possibility of a
      beneficial or harmful effect of MT in alcoholic liver disease or in other
      forms of liver disease for that matter. Evidence show how much effects of
      medical intervention may change over time. Ioannidis and Lau (61) applied
      "recursive cumulative meta-analyses" of randomized clinical trials to
      evaluate the relative change in the pooled treatment effect over time for 60
      medical interventions within pregnancy/perinatal medicine and cardiology.
      When 2,000 patients have been randomized, the pooled RR may change by a
      factor 0.7 to 1.3. At present, only about 1,000 patients with alcoholic
      liver disease and/or hepatitis B and C have been randomized to MT versus
      placebo or no intervention. Second, we chose to include only alcoholic liver
      disease and viral liver disease in the review. The major reason is that
      viral and alcohol-related liver diseases frequently coexist in the same
      patient. Several trials were old and did not check for viral liver disease
      in patients with suspected alcoholic liver disease. Further, hepatitis B or
      C marker positivity was not an exclusion criterion for the entry of the
      patient in one of the trials on patients with alcoholic liver disease (50).
      Other liver diseases like non-alcoholic liver disease and toxic liver
      diseases should be considered in other reviews. Finally, the duration of
      treatment as well as the dosing and the preparation of MT varied. This may
      have caused variable intervention effects. However, none of our subgroup
      analyses revealed that these factors were responsible for our finding of
      lack of intervention effects.

      Among the randomized clinical trials reporting adverse drug events, MT
      appeared safe and well tolerated. We recognize it is difficult to interpret
      the risk of adverse events from the literature for several reasons (62).
      Events may be missed since search terms related to adverse events are often
      not indexed, and causality is difficult to discern when events are published
      in a case report or case series. Among the studies that we excluded were
      some randomized clinical trials considering 180 patients with unspecified
      form of liver diseases (63). MT seemed to be well tolerated in this trial,
      although adverse events have been reported in the literature (64).

      In conclusion, although MT constituents have been used as a medical
      intervention for more than 2,500 yr, there remains insufficient evidence to
      support or to refute its use for liver patients. We need to conduct
      high-quality, placebo-controlled randomized trials before MT or MT
      constituents can be advocated for patients with alcoholic and/or viral liver
      disease.


      RESULTS

      Search Results

      We identified 1,833 references through electronic searches of The Cochrane
      Hepato-Biliary Group Controlled Trials Register (n = 40), The Cochrane
      Library (n = 75), and MEDLINE and EMBASE (n = 1,716) and through reading
      bibliographies (n = 2) (Fig. 1). Of these, 1,766 were in vitro studies,
      animal studies, studies unrelated to liver disease, duplicate reports, or on
      other patient types. Therefore, these references did not meet our inclusion
      criteria and were excluded. The remaining 67 publications were on patients
      with alcoholic and/or hepatitis B or C liver diseases treated with MT. Of
      these, 41 publications were excluded because they were observational studies
      or randomized trials that did not fulfil our inclusion criteria.
      Accordingly, 26 references referring to 13 randomized clinical trials could
      be included (30-55).

      Included Trials

      Eleven of the 13 randomized clinical trials were described in full paper
      articles (30, 31, 34, 39, 41, 44, 48-52) and two in abstract only (54, 55).

      The experimental treatment consisted of silymarin orally in 10 randomized
      clinical trials (30, 34, 39, 44, 48-52, 55); IdB1016 orally in two
      randomized clinical trials (IdB1016 is a lipophilic complex with silybin and
      phosphatidylcholine in a molar ratio of 1:1) (31, 54); and
      silybin-N2-cyclodextrin, a new oral formulation containing silybin, in one
      randomized clinical trial (41).

      The randomized clinical trials could be divided into four groups according
      to etiology:

      o chronic alcoholic liver disease included 657 patients, of which the
      majority had cirrhosis (30, 34, 39, 41, 44, 48, 51, 52, 55);
      o hepatitis B included 8 patients with acute hepatitis B (49);
      o hepatitis C included 10 patients with chronic hepatitis C (54);
      o alcoholic and/or hepatitis B or C liver diseases (31, 50), of which
      one trial included 20 patients with hepatitis B and hepatitis C (31) and the
      other included 200 patients with alcoholic liver disease with or without HCV
      antibody positivity (50). Anti-HCV antibodies were positive in 29 (13
      receiving MT and 16 receiving placebo) of the 75 patients for whom stored
      sera were available after completion of the trial (50).

      Excluded Studies

      A total of 33 studies on MT for liver diseases, described in 43 publications
      (available on request), were excluded mainly because they were observational
      studies or case series.

      Methodological Quality of Included Trials

      Only one (51) of the 13 randomized clinical trials provided a sample size
      estimation that was based on liver histology.

      The method to generate the allocation sequence was considered adequate in
      six (46.2%) of the trials (30, 39, 41, 44, 50, 51).

      Only three (23.1%) of the trials described adequate allocation concealment
      (44, 50, 51).

      All but one of the trials (52) were described as double blinded (92.3%).
      However, only six (46.2%) trials described the use of placebo with identical
      presentation in the control arm (31, 39, 41, 44, 50, 51). None of the trials
      checked the success of blinding.

      There was a fair description of follow-up and withdrawals/drop-outs in 12
      (92.3%) trials (30, 31, 34, 39, 41, 44, 48-52, 54). None of the trials
      stated that they used an intention-to-treat method to evaluate their data.
      All the trials but three (30, 41, 44) presumably used intention-to-treat
      analysis.

      All-Cause Mortality

      Combining the results of the 13 randomized clinical trials demonstrated no
      significant effect of MT given for a median duration of 6 months (range 1 wk
      to 41 months) on all-cause mortality (RR 0.78, 95% CI 0.53-1.15). There was
      no significant heterogeneity (I2= 5.9%). In the MT group, 36/456 (7.9%)
      patients died versus 45/459 (9.8%) patients in the control group (Fig. 2).

      Subgroup analyses stratifying the randomized clinical trials according to
      the single methodological quality components (generation of the allocation
      sequence, allocation concealment, blinding, and follow-up) did not
      demonstrate significant differences regarding the effect of MT on all-cause
      mortality between trials with and without adequate methodology.

      Subgroup analysis stratifying the randomized clinical trials into trials
      with all components adequate, trials having some components adequate, and
      trials without any of components adequate (not estimable since no events
      occurred in this group) (Fig. 3), did not demonstrate significant effects of
      MT on all-cause mortality.

      MT did not significantly influence all-cause mortality in the trials with a
      treatment duration less than 6 months (RR 0.35; 95% CI 0.04-3.22) or in the
      trials with a duration of treatment of at least 6 months (RR 0.81, 95% CI
      0.54-1.20); or in the trials including patients with chronic liver disease
      (data not shown); the RR in the trials including patients with acute liver
      disease was not estimable since no events occurred in this group. A
      worst-case scenario analysis considering all patients who dropped out or
      were withdrawn dead did not find a significant effect of MT (RR 1.09; 95% CI
      0.75-1.58). None of the trials reported mortality data distributed on Child
      class or other prognostic classification.

      MT significantly decreased all-cause mortality in patients with alcoholic
      liver disease (RR 0.58, 95% CI 0.34-0.98; p= 0.04) (30, 34, 39, 41, 44, 48,
      51, 52, 55). There was no significant heterogeneity (I2= 0%). In the MT
      group 16/325 (4.9%) patients died versus 28/332 (8.4%) in the control group.
      This finding could not be confirmed nor refuted in two high-quality trials
      (RR 0.34, 95% CI 0.06-2.11) (44, 51).

      In patients with alcoholic liver disease or alcoholic liver disease with HCV
      antibody positivity (50), MT demonstrated no significant effect on all-cause
      mortality (RR 1.11, 95% CI 0.62-1.99). In the MT group 20/103 (19.4%)
      patients died versus 17/97 (17.5%) in the control group. In patients with
      hepatitis B (49) none of the patients died out of the 13 in the MT and 15 in
      the control group. In patients with hepatitis C (54) none of the patients
      died out of the 5 in the MT and 5 in the control group. In patients with
      hepatitis B and hepatitis C (31) none of the patients died out of the 10 in
      the MT and 10 in the control group.

      Liver-Related Mortality

      Among the 13 trials only four reported liver-related mortality (Fig. 4) (39,
      44, 50, 51). Three of the trials included patients with alcoholic liver
      disease (39, 44, 51) and the Pares et al. trial included patients with
      alcoholic liver disease or alcoholic liver disease with HCV antibody
      positivity (50). These trials found a significant effect of MT on
      liver-related mortality (RR 0.50, 95% CI 0.29-0.88; p= 0.02). There was no
      significant heterogeneity (I2= 0%). In the MT group, 16/422 (3.8%) patients
      died versus 31/422 (7.3%) patients in the control group.

      Subgroup analysis demonstrated no significant effect of MT on liver-related
      mortality in the three trials having all four methodological components
      adequate (RR 0.57, 95% CI 0.28-1.19) whereas MT significantly decreased
      mortality in the trials having only one or more components adequate (RR
      0.41, 95% CI 0.17-0.97). This effect was based on only one trial with less
      than 100 patients randomized (39). There was no significant difference
      between the two estimates (test of interaction z = 0.57). The effect of MT
      on liver-related deaths in the trials with no adequate methodological
      component was not estimable due to any deaths. A worst-case scenario
      analysis of patients with alcoholic liver disease (all patients who
      dropped-out or were withdrawn were considered dead) changed the estimate to
      no significant effect of MT on liver-related mortality (RR 0.81, 95% CI
      0.58-1.13).

      Liver-Related Complications

      In the only trial reporting individual liver-related complications, MT did
      not significantly affect the incidence of patients with ascites, hepatic
      encephalopathy, or gastro-intestinal bleeding (50). MT demonstrated no
      significant effect on combined liver-related complications (44, 50).

      Liver Biochemistry and Liver Histology

      MT significantly decreased s-bilirubin concentration and GGT activity in
      both fixed effect and random effects model analyses:

      o s-bilirubin: WMD -4.68 N<mol/L (95% CI -7.72 to -1.64 N<mol/L; p<
      0.05) (fixed effect model). There was no significant heterogeneity (I2= 0%)
      o GGT: WMD -26.80 U/L (95% CI -32.86 to -20.73 U/L; p< 0.05) (fixed
      effect model). There was significant heterogeneity (I2= 68%).

      MT showed a significant beneficial effect on AST and ALT when analyzed by
      the fixed effect model, but not in the random effects model. MT did not
      significantly influence prothrombin or s-albumin. There were no significant
      effects of MT on liver biopsy findings in the only trial reporting this
      outcome (51).

      Adverse Events

      In the MT group 0/456 patients had serious adverse events versus 0/459
      patient in the control group. MT did not significantly affect the occurrence
      of non-serious adverse events (RR 0.83, 95% CI 0.46-1.50). In the MT group,
      16/456 (3.5%) patients had non-serious adverse events versus 20/459 (4.4%)
      patients in the control group. The adverse events observed in the MT group
      encompassed impotence (one patient), pruritus (four patients), cephalea
      (three patients), and nausea (one patient). The authors did not report the
      type of adverse event in seven patients. The adverse events observed in the
      control group were pruritus (11 patients), cephalea (four patients), and
      nausea (one patient). The authors did not report the type of adverse events
      in four patients.

      PATIENTS AND METHODS

      Inclusion Criteria

      We applied The Cochrane Collaboration methodology (21) and followed our
      predefined, peer-reviewed, published Cochrane Hepato-Biliary Group protocol
      (22). Only randomized clinical trials were included (22). Patients with
      alcoholic liver cirrhosis, liver fibrosis, hepatitis, and/or steatosis as
      well as patients with viral induced liver disease (hepatitis B and/or
      hepatitis C) according to the diagnostic work-up used in the individual
      trial were included (22). The trials should have administered MT or any MT
      constituent at any dose or duration versus placebo or no intervention (22).

      Types of Outcome Measures

      The primary outcome measure was the number of patients dying (22). Secondary
      outcomes measures were the development of clinical symptoms and
      complications analyzed separately and combined, liver biochemistry, liver
      biopsy findings, as well as number and type of adverse events (22).

      Search Strategy for Trials

      The following databases were searched: The Cochrane Hepato-Biliary Group
      Controlled Trials Register (December 2003), The Cochrane Central Register of
      Controlled Trials on The Cochrane Library (Issue 4, 2003), MEDLINE (1966 to
      December 2003), and EMBASE (1974 to December 2003) using the search terms
      "milk thistle" or "silymarin" or "silybin" or "silibinin" or "silydianin" or
      "silychristin" or commercial names (LegalonB., SilipideB., RealsilB.,
      CarsilB., SiliphosB.) and "liver disease" or "alcoholic liver disease" or
      "viral liver disease" or "hepatitis B" or "hepatitis C" (22). The MEDLINE
      search was combined with the search strategy of The Cochrane Hepato-Biliary
      Group (23).

      The principal authors of the identified trials were approached and inquired
      about additional randomized clinical trials. Pharmaceutical companies
      involved in the production of MT products were contacted in order to obtain
      unidentified published or unpublished randomized clinical trials.

      Patient Characteristics, Diagnosis, and Interventions

      The following items were recorded from the individual randomized clinical
      trials: mean (or median) age, sex ratio, liver disease according to the
      etiology, duration of liver disease, severity of liver disease at entry,
      alcohol consumption at entry, type and dose of MT-intervention, and type of
      control intervention. Development of clinical symptoms and complications,
      liver biochemistry (serum (s)-bilirubin, prothrombin time, s-albumin,
      s-aspartate aminotransferase (AST), s-alanine aminotransferase (ALT),
      s-alkaline phosphatases (AP), s-gamma-glutamyl transferase (GGT)), liver
      biopsy findings, alcohol consumption, quality of life, and adverse events
      during follow-up were registered.

      Assessment of Methodological Quality

      The methodological quality of the randomized clinical trials was assessed
      using individual components of methodological quality (22, 24-26). We
      registered whether the randomized clinical trial reported the use of
      intention-to-treat analysis, i.e., all patients randomized must be retained
      in the trial (22). Data on the number of patients with each outcome by
      allocated treatment group, irrespective of compliance of follow-up, were
      sought to allow an intention-to-treat analysis.

      Statistical Analyses

      The meta-analyses were performed in Review Manager Software (version 4.2.7)
      from The Cochrane Collaboration (http://www.cochrane.org). We examined all
      outcomes with both the random effects model and the fixed effect model (27,
      28). Dichotomous data were analyzed by calculating the relative risk (RR)
      and continuous outcomes as weighed mean difference (WMD), both with 95%
      confidence intervals (CI). Heterogeneity was examined by the O2 test (p<
      0.1) and a useful statistic for quantifying inconsistency (I2=[(Q -
      df )/Q]C 100%, where Q is the O2 statistic and df is its degrees of
      freedom) (29). Potential causes for heterogeneity were explored by
      performing subgroup analyses.



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