Re: What does is take to convince the Cochrane Hepatobiliary Group?

[Guest guest]

Dave, I also find it disturbing. Interesting that they say it is significantly associated with weight gain.I haven't heard anyone in our group saying they have gained weight on urso, have you?LeeIt is really disturbing to me that after all this time (20 years of research!) no benefit of URSO can be found in primary biliary cirrhosis by the Cochrane Hepatobiliary Group: ___________UDCA did not improve pruritus, fatigue, autoimmune conditions, liver histology, or portal pressure. UDCA seemed to improve biochemical variables, such as serum bilirubin, and ascites and jaundice, but the findings were based on few trials with sparse data. The use of UDCA was significantly associated with adverse events, mainly weight gain.CONCLUSIONS: This updated systematic review did not demonstrate any benefit of UDCA on mortality and mortality or liver transplantation in patients with PBC.

[Guest guest]

Hi Lee;

I'll try to get the full paper from the Cochrane Hepatobiliary Group

today, but just reading the abstract it's difficult to reconcile

their summary with reports like this:

_________________

Am J Gastroenterol. 2006 Sep;101(9):2044-50.

Prognosis of ursodeoxycholic acid-treated patients with primary

biliary cirrhosis. Results of a 10-yr cohort study involving 297

patients.

ter Borg PC, Schalm SW, Hansen BE, van Buuren HR; Dutch PBC Study

Group

Department of Gastroenterology and Hepatology, Erasmus Medical

Center, Rotterdam, The Netherlands.

BACKGROUND AND AIMS: The therapeutic potential of ursodeoxycholic

acid (UDCA) treatment in primary biliary cirrhosis (PBC) remains

controversial. In addition, relatively few data have been reported on

the outcome of patients who have been treated long term. The aim of

the present study was to document long-term survival of a

prospectively followed large cohort of UDCA treated patients in

comparison to that predicted by the Mayo model and of a matched

control cohort of the Dutch population. METHODS: Two hundred ninety-

seven patients were included and followed during a median period of

68 (range 3-126) months until death or the end of the study. RESULTS:

Survival free of transplantation (1 yr 99.7%, 5 yr 87%, and 10 yr

71%) was significantly better than predicted by the Mayo model (p=

0.01). However, for patients with abnormal serum bilirubin and/or

albumin concentrations at entry, observed and predicted survival did

not significantly differ. Compared with survival for a standardized

cohort of the Dutch population, observed survival for the total group

was significantly decreased (p= 0.0003); for noncirrhotic patients

and patients with normal entry bilirubin and albumin concentrations

survival was comparable. Serum bilirubin and albumin concentrations

were the prognostic factors most consistently associated with

survival. CONCLUSIONS: A 10-year prognosis for most UDCA-treated

patients with PBC, i.e., those with a normal bilirubin and albumin

concentration, is comparable to that of a matched general population.

Our finding that observed survival was significantly better than

predicted by the Mayo model may suggest that this model did not

accurately predict prognosis in our cohort. Alternatively, this

finding indicates an important therapeutic effect of long-term UDCA

treatment in PBC, particularly in patients with noncirrhotic,

nonadvanced disease. PMID: 16848809.

_________________

Gastroenterology. 2006 Mar;130(3):715-20.

Excellent long-term survival in patients with primary biliary

cirrhosis and biochemical response to ursodeoxycholic acid.

Pares A, Caballeria L, Rodes J

Liver Unit, Digestive Diseases Institute, Hospital Clinic, IDIBAPS,

Barcelona, Spain. pares@...

BACKGROUND & AIMS: Because the efficacy of UDCA on long-term outcome

of primary biliary cirrhosis (PBC) has not been completely

elucidated, we have assessed the course and survival of patients with

PBC treated with UDCA and compared with the survival predicted by the

Mayo model and the estimated survival of a standardized population.

METHODS: (One hundred ninety-two patients [181 women] with PBC

treated with UDCA [15 mg/kg per day] for 1.5-14 years.) Response to

treatment was defined by an alkaline phosphatase decrease greater

than 40% of baseline values or normal levels after 1 year of

treatment. The predicted survival was obtained by the Mayo model and

the estimated survival was taken from the standardized matched

Spanish population. RESULTS: Seventeen patients died or fulfilled

criteria for liver transplantation (8.9%). The observed survival was

higher than that predicted by the Mayo model and lower than that of

the control population (P < .001). One hundred seventeen patients

(61%) responded to treatment. The survival of responders was

significantly higher than that predicted by the Mayo model and

similar to that estimated for the control population (P = .15). By

contrast, the survival of patients without biochemical response was

lower than that estimated for the Spanish population (P < .001)

although higher than that predicted by the Mayo model. CONCLUSIONS:

Biochemical response to UDCA after 1 year is associated with a

similar survival to the matched control population, clearly

supporting the favorable effects of this treatment in PBC. The

suboptimal survival of nonresponders identifies the group for further

treatments. PMID: 16530513.

_________________

Z Gastroenterol. 2005 Sep;43(9):1051-9.

Ursodeoxycholic acid in the therapy for primary biliary cirrhosis:

effects on progression and prognosis.

Leuschner U, Manns MP, Eisebitt R

Medizinische Klinik der Johann Wolfgang Goethe Universitat, furt

am Main, Germany. U.Leuschner@...

The effects in clinical studies of UDCA on the endpoints " death "

or " pre-transplantation survival " can only be shown when UDCA therapy

is started in an early disease phase, preferably in stage I but no

later than stage II, and is then continued into stages III/IV, or

preferably stage IV. The reasons for this lie in the observation

that, in stages I/II, no patient suffers from progressive disease

that irrevocably leads to death or transplantation, while a

measurable effect of UDCA, as is true for other drugs and other

hepatic diseases, continues to dwindle and finally disappears as

patients progress through the fibrotic and cirrhotic stages III and

IV. Hence, administration of UDCA must begin in the phase of

progressive inflammation (stages I and II) and the outcome documented

after many years of long-term therapy. This requires very large,

probably unattainable, patient collectives. Whether it is justified

to administer placebo to one-half of these patients over such an

extended period of time represents a profound ethical dilemma.

Because these arguments were not considered in the two meta-analyses

cited above or in any other study, they do not allow a definitive

statement on the life expectancy of patients on UDCA therapy. On the

other hand, it is possible using generally accepted, independent

prognostic variables and mathematical models, whose limitations are

well-known and must be considered, to predict with a high degree of

accuracy the disease course of treated and untreated patients and

calculate their life expectancy and/or pre-transplantation survival.

Because UDCA exerts a significant positive effect on the most

important prognostic markers for PBC, such as serum bilirubin,

piecemeal necroses, histological disease progression, ascites and

edema, and apparently the scores for pruritus and fatigue, this

permits us to demonstrate not only a decrease in the incidence of

transplantation but also to calculate a prolongation in life

expectancy. PMID: 16142614.

_________________

The Cochrane Hepatobiliary Group report is disturbing because it

could potentially make it harder for stage I and II PBCers to get

prescriptions of ursodiol.

No I have never heard of the weight gain " adverse effect " of ursodiol

before.

Best regards,

Dave R.

[Guest guest]

Thanks Dave,Something seems amiss. Something just seems off in the Cochrane paper.Even the statement about weight gain just seems out of left field. That's why I mentioned it.These papers are more in line with what we have read previously.We really do need more research. More data, more trials. LeeHi Lee;I'll try to get the full paper from the Cochrane Hepatobiliary Group today, but just reading the abstract it's difficult to reconcile their summary with reports like this:_________________Am J Gastroenterol. 2006 Sep;101(9):2044-50. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients.

[Guest guest]

-----Original

Message-----

CONCLUSIONS: This updated review did not demonstrate any benefit

of UDCA on mortality and mortality

More trials than not, have come up with the same conclusion.

But….. Is it possible the Dutch, German, Spain & UK studies

yield different conclusions, because PSC is different there? (They seem to have a longer - less benign

disease.) Several studies have

sighted the difference between PSC here in the US vs. other

countries. Maybe their results are

different because they shouldn’t be using the Mayo model.

I still think they are spending too much time trying to

prove URSO’s worth and are doing it to the detriment of other, newer

drugs. I understand where their coming

from, it lowers LFT’s so it *has*

to be doing something good, but without proof, they need to move on and try

something new.

Just my 2 cents, Barb in Texas

[Guest guest]

The article states that " Over half of the trials had high risk of bias. " I would

like to see those trials eliminated, then see what the data says. I also wonder

what they used to determine high risk of bias.

Just my 2 cents worth!

, if you have trouble getting teh full article let me know, I can probably

get it.

LINDA

-------------- Original message ----------------------

> It is really disturbing to me that after all this time (20 years of

> research!) no benefit of URSO can be found in primary biliary

> cirrhosis by the Cochrane Hepatobiliary Group:

> ____________________

>

> Yan Gong M.D., M.I.H., Zhibi Huang M.P.H., Christensen M.D., Dr.

> Med.Sci., Christian Gluud M.D., Dr. Med.Sci.

>

> Ursodeoxycholic Acid for Patients With Primary Biliary Cirrhosis: An

> Updated Systematic Review and Meta-Analysis of Randomized Clinical

> Trials Using Bayesian Approach as Sensitivity Analyses

>

> The American Journal of Gastroenterology (OnlineEarly Articles).

> doi:10.1111/j.1572-0241.2007.01235.x

>

> CLINICAL REVIEW

> Ursodeoxycholic Acid for Patients With Primary Biliary Cirrhosis: An

> Updated Systematic Review and Meta-Analysis of Randomized Clinical

> Trials Using Bayesian Approach as Sensitivity Analyses

> Yan Gong, M.D., M.I.H.11The Cochrane Hepato-Biliary Group, Copenhagen

> Trial Unit, Center for Clinical Intervention Research, Department

> 7102, Rigshospitalet, Copenhagen University Hospital, Copenhagen,

> Denmark, Zhibi Huang, M.P.H.22Department of Epidemiology, Institute

> of Public Health, Copenhagen University, Copenhagen, Denmark,

> Christensen, M.D., Dr. Med.Sci.33Clinic of Internal Medicine I, H:S

> Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen,

> Denmark, and Christian Gluud, M.D., Dr. Med.Sci.11The Cochrane Hepato-

> Biliary Group, Copenhagen Trial Unit, Center for Clinical

> Intervention Research, Department 7102, Rigshospitalet, Copenhagen

> University Hospital, Copenhagen, Denmark1The Cochrane Hepato-Biliary

> Group, Copenhagen Trial Unit, Center for Clinical Intervention

> Research, Department 7102, Rigshospitalet, Copenhagen University

> Hospital, Copenhagen, Denmark; 2Department of Epidemiology, Institute

> of Public Health, Copenhagen University, Copenhagen, Denmark; and

> 3Clinic of Internal Medicine I, H:S Bispebjerg Hospital, Copenhagen

> University Hospital, Copenhagen, Denmark

> Reprint requests and correspondence: Yan Gong, M.D., M.I.H., The

> Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for

> Clinical Intervention Research, Department 33.44, Rigshospitalet,

> Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen,

> Denmark.

>

> Abstract

> OBJECTIVES: Ursodeoxycholic acid (UDCA) is used for primary biliary

> cirrhosis (PBC), but the beneficial effects remain controversial.

>

> METHODS: We performed an updated systematic review to evaluate the

> benefits and harms of UDCA in patients with PBC. We included

> randomized clinical trials evaluating UDCA versus placebo or no

> intervention in patients with PBC. The primary outcomes, mortality

> and mortality or liver transplantation, were reported as relative

> risk (RR) with 95% confidence interval (CI). Meta-regression was used

> to investigate the associations between UDCA effects and the trial's

> risk of bias, UDCA dose, duration, and PBC severity at trial entry.

> We used Bayesian meta-analytic approaches as sensitivity analyses.

>

> RESULTS: Sixteen randomized clinical trials (1,447 patients)

> evaluating UDCA versus placebo or no intervention were identified.

> Over half of the trials had high risk of bias. Comparing with placebo

> or no intervention, UDCA did not significantly affect mortality (RR

> 0.97, 95% CI 0.67–1.42) and mortality or liver transplantation (RR

> 0.92, 95% CI 0.71–1.21). The findings were supported by the Bayesian

> meta-analyses. Meta-regression analyses suggested that UDCA effects

> seem to be associated with patient's disease severity and trial

> duration. UDCA did not improve pruritus, fatigue, autoimmune

> conditions, liver histology, or portal pressure. UDCA seemed to

> improve biochemical variables, such as serum bilirubin, and ascites

> and jaundice, but the findings were based on few trials with sparse

> data. The use of UDCA was significantly associated with adverse

> events, mainly weight gain.

>

> CONCLUSIONS: This updated systematic review did not demonstrate any

> benefit of UDCA on mortality and mortality or liver transplantation

> in patients with PBC.

> ____________________

>

> Dave

> (father of (21); PSC 07/03; UC 08/03)

>

>

>

>

It is really disturbing to me that after all this time (20 years of

research!) no benefit of URSO can be found in primary biliary

cirrhosis by the Cochrane Hepatobiliary Group:

____________________

Yan Gong M.D., M.I.H., Zhibi Huang M.P.H., Christensen M.D., Dr.

Med.Sci., Christian Gluud M.D., Dr. Med.Sci.

Ursodeoxycholic Acid for Patients With Primary Biliary Cirrhosis: An

Updated Systematic Review and Meta-Analysis of Randomized Clinical

Trials Using Bayesian Approach as Sensitivity Analyses

The American Journal of Gastroenterology (OnlineEarly Articles).

doi:10.1111/j.1572-0241.2007.01235.x

CLINICAL REVIEW

Ursodeoxycholic Acid for Patients With Primary Biliary Cirrhosis: An

Updated Systematic Review and Meta-Analysis of Randomized Clinical

Trials Using Bayesian Approach as Sensitivity Analyses

Yan Gong, M.D., M.I.H.11The Cochrane Hepato-Biliary Group, Copenhagen

Trial Unit, Center for Clinical Intervention Research, Department

7102, Rigshospitalet, Copenhagen University Hospital, Copenhagen,

Denmark, Zhibi Huang, M.P.H.22Department of Epidemiology, Institute

of Public Health, Copenhagen University, Copenhagen, Denmark,

Christensen, M.D., Dr. Med.Sci.33Clinic of Internal Medicine I, H:S

Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen,

Denmark, and Christian Gluud, M.D., Dr. Med.Sci.11The Cochrane Hepato-

Biliary Group, Copenhagen Trial Unit, Center for Clinical

Intervention Research, Department 7102, Rigshospitalet, Copenhagen

University Hospital, Copenhagen, Denmark1The Cochrane Hepato-Biliary

Group, Copenhagen Trial Unit, Center for Clinical Intervention

Research, Department 7102, Rigshospitalet, Copenhagen University

Hospital, Copenhagen, Denmark; 2Department of Epidemiology, Institute

of Public Health, Copenhagen University, Copenhagen, Denmark; and

3Clinic of Internal Medicine I, H:S Bispebjerg Hospital, Copenhagen

University Hospital, Copenhagen, Denmark

Reprint requests and correspondence: Yan Gong, M.D., M.I.H., The

Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for

Clinical Intervention Research, Department 33.44, Rigshospitalet,

Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen,

Denmark.

Abstract

OBJECTIVES: Ursodeoxycholic acid (UDCA) is used for primary biliary

cirrhosis (PBC), but the beneficial effects remain controversial.

METHODS: We performed an updated systematic review to evaluate the

benefits and harms of UDCA in patients with PBC. We included

randomized clinical trials evaluating UDCA versus placebo or no

intervention in patients with PBC. The primary outcomes, mortality

and mortality or liver transplantation, were reported as relative

risk (RR) with 95% confidence interval (CI). Meta-regression was used

to investigate the associations between UDCA effects and the trial's

risk of bias, UDCA dose, duration, and PBC severity at trial entry.

We used Bayesian meta-analytic approaches as sensitivity analyses.

RESULTS: Sixteen randomized clinical trials (1,447 patients)

evaluating UDCA versus placebo or no intervention were identified.

Over half of the trials had high risk of bias. Comparing with placebo

or no intervention, UDCA did not significantly affect mortality (RR

0.97, 95% CI 0.67–1.42) and mortality or liver transplantation (RR

0.92, 95% CI 0.71–1.21). The findings were supported by the Bayesian

meta-analyses. Meta-regression analyses suggested that UDCA effects

seem to be associated with patient's disease severity and trial

duration. UDCA did not improve pruritus, fatigue, autoimmune

conditions, liver histology, or portal pressure. UDCA seemed to

improve biochemical variables, such as serum bilirubin, and ascites

and jaundice, but the findings were based on few trials with sparse

data. The use of UDCA was significantly associated with adverse

events, mainly weight gain.

CONCLUSIONS: This updated systematic review did not demonstrate any

benefit of UDCA on mortality and mortality or liver transplantation

in patients with PBC.

____________________

Dave

(father of (21); PSC 07/03; UC 08/03)

[Guest guest]

,

You are right the Cochrane reviews are stingy. I recieve their

quarterly reviews and it is always interesting reading. They review

the literature and throw out any studies that might be questionable.

They try to be very objective. They function on the prospect that

something is unproven until it is proven pretty convincingly. Its sort

of takes the presumption that things don't work. It's a great resource

for quickly finding which things have been pretty well proven. Again

it's great as long as you understand their methods and point of view.

The problem is that insurance companies can use their reports to deny

benifits that might work but haven't been proven beyond a resonable

doubt.

My recollection is that 70% of their reviews find no benifit for

treatments that they review.

I'm glad that my father in law didn't ask for a Cochrane review when I

asked permission to marry his daughter because I wouldn't have passed.

I think that serve an important purpose in scrutinizing treatments that

are offered.

[Guest guest]

They were evaluating urso for primary billiary cirrhosis not PSC.

It " works " better in PBC compared to PSC. Since URSO there have been

fewer transplants needed for PBC. No hepatologist in their right mind

would refuse URSO for PBC. None of the PSC URSO studies have shown

improved mortality, or transplant rates so the Cochrane group would

never endorse URSO for PSC unless there was more convincing data.

>

> -----Original Message-----

> CONCLUSIONS: This updated review did not demonstrate any benefit of

UDCA

> on mortality and mortality

>

> More trials than not, have come up with the same conclusion.

But... Is

> it possible the Dutch, German, Spain & UK studies yield different

> conclusions, because PSC is different there? (They seem to have a

> longer - less benign disease.) Several studies have sighted the

> difference between PSC here in the US vs. other countries. Maybe

their

> results are different because they shouldn't be using the Mayo

model.

>

> I still think they are spending too much time trying to prove URSO's

> worth and are doing it to the detriment of other, newer drugs. I

> understand where their coming from, it lowers LFT's so it *has* to

be

> doing something good, but without proof, they need to move on and

try

> something new.

>

> Just my 2 cents, Barb in Texas

>

[Guest guest]

leedeubert wrote:

>

> Dave, I also find it disturbing. Interesting that they say it is

> significantly associated with weight gain.

> I haven't heard anyone in our group saying they have gained weight on

> urso, have you?

I guess it's a good thing I couldn't tolerate the Urso, then. LOL!! I

gained enough with 5 years of prednisone!!

Regards,

Carolyn B. in SC

[Guest guest]

I once asked my GP if Urso can cause

weight gain. He said he didn't think so, but later he told me it might be

possible since Urso improves the flow of bile and thus the absorption of fat.

From:

[mailto: ] On Behalf Of noneenator@...

Sent: Thursday, April 26, 2007

02:09

To:

Subject: Re: What

does is take to convince the Cochrane Hepatobiliary Group?

i gained about 20 lbs or more on

urso. i hardly eat but never lose weight.