Share Facebook
Crohn's Disease Forum » Treatment » Imuran/Azathioprine/6-MP » Questioning An Azathioprine Withdrawal Study


08-27-2012, 04:34 PM   #1
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Questioning An Azathioprine Withdrawal Study

I posted a piece called Questioning An Azathioprine Withdrawal Study on my blog yesterday and I just wanted to let people here in crohnsforum know about it.

It will probably be covered by David Healy's (author of Pharmageddon) blog or RxISK.org in the next few days. I got really positive feed back from him this morning.
08-27-2012, 06:25 PM   #2
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
I'm curious if you actually read the entire study rather than just the abstract? I ask this because you aren't using the actual number of people in each group who finished the study in your calculations which throws off every calculation and subsequent argument you made.
08-27-2012, 09:36 PM   #3
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Yeah, I read the whole paper. The argument is the same. There were only a couple of people who dropped out of each group. I think 2. And btw if you redo their stats (which I left out) they actually make a Type II error. Their math is actually worse than it appears.
08-27-2012, 09:47 PM   #4
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
I think what you mention about quality of life is something that should be taken into account though their not mentioning it isn't bad science like you claim. But doctors and patients need to have quality of life related discussions, you're right about taking that variable into account.

Azathioprine long term is an infinitely complex issue that dissertations could no doubt be written on. One issue with the study is they used an endpoint of CDAI of greater than 250 as relapse. If someone is in remission from Azathioprine, because Azathioprine has been shown to lead to mucosal healing in many, I can see it taking quite awhile for degradation to the point of a greater than 250 score to take place. How many of those people relapsed at 20 months? 24 months? Or how many had inflammation start back up that is slowly causing fibrosis of their intestinal tract but no other symptoms and one day they're going to wake up in the middle of the night with an obstruction and wonder where that came from?

In my opinion, utilizing just the CDAI without endoscopic evaluation really doesn't tell us the whole story. I'd bet good money that a lot more of those placebos were on their way to relapse than we realize.

Now, I hate medications. I don't want to see anyone on Azathioprine. But for some, it's the right answer and saying everyone should get off it or everyone should stay on it past 3.5 years goes against what we know about Crohn's. And that is everyone is different and needs to be properly evaluated and closely monitored to determine what is best for them via a ton of different variables.

Crohn's disease is so very complex. These studies are never going to give us the full picture and they'll never be perfect. But they can give us data that a good doctor can utilize, in part, to help plot the best course of action for a patient based upon their novel circumstance.
08-27-2012, 10:04 PM   #5
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Oh David, it's exactly bad science and completely irresponsible.
08-27-2012, 10:06 PM   #6
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
How is it bad science? That's not what they were studying.
08-27-2012, 10:10 PM   #7
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
This brings me to questions about methodology and resourcefulness. The paper acknowledges that azathioprine has side effects but it makes no attempt to quantify them. What they could have done, which is simple and extremely useful, is to ask the study participants at the end of the trial if they though they were in the placebo group or not. It’s crazy to me the researchers overlook this. Participants could also be asked if their quality of life improved during the trial. Possibly that’s actually the most important thing of all! Suppose 79% of participants in the placebo group said their quality of life improved while no one in the azathioprine group did. (Those aren’t made up numbers btw, it’s what we’d expect from a placebo group who no longer suffers the side effects of azathioprine and who didn’t relapse. It’s also possible, thought unlikely, for someone who did relapse to report that their quality of life improved. This would happen if the side effects were worse than the relapse.) But alas, this information is MIA. But why? Quantifying side effects should mean a lot to a study about a drug. It could always turn out that side effects are worse than treatment. These researchers completely ignore this possibility. Bad science.
Not asking that question isn't bad science. They're just not doing the study you want based upon your experiences. I agree that it would be interesting, but not doing so doesn't make it bad science.
08-27-2012, 11:33 PM   #8
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Nope, but thanks for reading the post. I appreciate it. A one line conclusion to such a complex question as continuing with azathioprine treatment is patently ridiculous. A responsible conclusion should either consider the side effects or acknowledge they don't really know enough to make a recommendation. They did neither.
08-27-2012, 11:57 PM   #9
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
I again have to question whether you read the entire study as they DO showcase that they took potential side effects into account in making their recommendation:

This
limit was, however, considered clinically relevant at the
time of the conception of the trial on the basis of the
benefit/risk ratio for patients receiving long-term treatment
with thiopurines, taking into account the consequences
of relapse and the possibility of re-treating the
patient with azathioprine in case of relapse on the one
hand and the potential risks of long-term treatment on
the other hand. Choosing a limit lower than 20% would
have led to the same conclusion, but the power level
would have been much lower.
Discussion regarding the duration of an effective azathioprine
treatment mainly concerns 2 points: (1) the
magnitude of the relapse risk after stopping the drug and
(2) the toxicity of a prolonged treatment.
Whether prolonged azathioprine/6-mercaptopurine
treatment carries specific risks that are different from
those during shorter therapies, especially in terms of
bone marrow suppression, infections, and lymphoma, is
unclear.
Previous evaluation of long-term azathioprine/
6-mercaptopurine toxicity showed that the bulk of adverse
effects occurred in the first year of treatment and
very few beyond the sixth year,10 even though rare cases
of severe bone marrow toxicity may occur abruptly at any
time up to 11 years of treatment.18 Infections do not
seem to be more frequent in long-term treatment.10 The
issue of whether prolonged therapy with azathioprine/6-
mercaptopurine induces a significant risk of lymphoma
in inflammatory bowel disease is blurred by several incompletely
answered questions. The baseline—independent
of treatment—lymphoma rate in inflammatory
bowel disease remains debated.29–31 Whether thiopurines
increase the lymphoma risk in Crohn’s disease,
irrespective of treatment duration, is also controversial.
8,9,14,32,33 A recent meta-analysis of 6 reported studies
suggests a 4-fold increase in the relative risk.15 In addition,
some lymphoma cases seem clearly linked to immunosuppressive
therapy.5,11–13,34,35
Identification of factors predictive of relapse among
baseline data would be helpful for selecting candidates
for azathioprine continuation or discontinuation. Two
biological markers, C-reactive protein and hemoglobin,
were found in our multivariate analysis to be associated
with a higher relapse rate in the 18 following months. Of
interest, an increased C-reactive protein level had been
previously shown, in several studies, to predict relapse in
Crohn’s disease patients with medically induced remission.
36,37 Smoking status (which is regarded as strong predictor of poor outcome in Crohn’s disease38), the
presence of ileocolonic residual lesions or ulcerations at
endoscopy, and the duration of azathioprine administration
before inclusion (but all the patients had a duration
of treatment longer than 3.5 years) were not predictive of
relapse in this study. Even if the proportion of patients
who have a colonoscopy at baseline is relatively limited
(54%), the latter result does not support the concept that
mucosal healing could be used as a marker for prediction
of stable remission. The mean CDEIS level was remarkably
low at baseline, but only 36% of patients had
complete mucosal healing (CDEIS of 0): ulcerations were
still present in 47% of the patients with residual lesions.
kss said:
A responsible conclusion should either consider the side effects or acknowledge they don't really know enough to make a recommendation. They did neither.
They did both.
08-28-2012, 12:09 AM   #10
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
For the record, I think it's absolutely fantastic what you're doing. We just have to be very careful and discerning when reading studies. Studies can be very hard to read and god knows I'm still learning how to do so and have a long way to go. I find that it's easy for me to interpret a study how I want to and am having to teach myself to be emotionally and intellectually neutral as I read them. It's tough though. I hope you continue to do stuff like this, it's great!
08-28-2012, 09:25 AM   #11
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Oh no. They asked not one patient in the study about their side effects. Not one. What you're confused by is the qualitative argument. It's hand waving about the prior art.
08-28-2012, 10:28 AM   #12
David
Co-Founder
 
David's Avatar
 
Join Date: Feb 2006
Location: Naples, Florida
Of course they did, thus the toxicity section. I have no doubt patients were monitored very closely. AND they utilized data from other studies in their discussion that resulted in the conclusion. If there were a tremendous amount of adverse events in their study, then that no doubt would have been reported in the toxicity section and their conclusion likely would have read, "Due to the large amount of adverse events..."

Every decent doctor will use studies like this as a STARTING POINT. If their patient has been on AZA for 5 years and is having a lot of side effects and their quality of life is low, then they're probably going to take them off. But if the patient isn't having side effects and the doctor is wanting data to help them determine what they should do long term, studies like this are great to so they can be educated when discussing treatment with their patient.
08-28-2012, 11:31 AM   #13
CLynn
Senior Member
 
CLynn's Avatar
 
Join Date: Feb 2012
Location: Missouri
kss, may I ask, are you Aza?
__________________
Cheryl
Diagnosed:1988
Previous meds: Sulfadiazine, Flagyl, Prednisone, Imuran, Pentasa, Asacol
Surgeries: re-section 2004
Currently taking: B-12 injections every 2 weeks, multi vitamin/mineral, fish oil (1000 mg), D3 (5000 mg)

Also lucky enough to have psoriasis as well.
06-23-2013, 09:49 AM   #14
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
This is sort of an old thread but I thought I'd update it with some new relevant information from the Cochrane Collaboration. They just released (May 31, 2013) a meta analysis on azathioprine and 6mp. Here's the link: Azathioprine or 6-mercaptopurine for the treatment of active Crohn's disease.

And CLynn I'm sorry I didn't respond. If you're asking if I'm taking azathioprine the answer is No. My personal experience is what my original blog post was about: stopping it against the advice of my physician and pointing out the withdrawal study I read was a very poor piece of work. My personal results make me feel justified but the Cochrane meta analysis is solid work which we should definitely be sharing. Getting rid of the side effects of azathioprine can be a really big deal!
06-23-2013, 10:13 AM   #15
kh216
Forum Monitor
 
Join Date: Jul 2012
Location: Barrington, New Jersey

My Support Groups:
I am at an interesting crossroads in my treatment. Presently, I am on 6mp and Lialda and I feel very good. The last time I had some minor issues was the middle of April. Here is my recent history: In Jan. of 2011, I had a colonscopy which revealed right sided inflammation at the colon and at the terminal ileium site. For the past two years, I was on varying dosages of 6mp. I was on Entocort for about a year and a couple of times I had to go on one week to two week bouts of Prednisone for flares. It has been over a year since I needed Prednisone and I am now off Entocort. However, the problem with 6mp is that my white blood count is too low. I just had another colonscopy this month which revealed that I had no more inflammation in my colon but nodular colitis in the terminal ileum. I have an appt with my GI doctor in August to discuss treatment options.
__________________
6mp
Lialda
Vitamin D and B 12
Calcium
06-23-2013, 10:34 AM   #16
kss
Senior Member
 
Join Date: Oct 2011
Location: Fort Collins, Colorado

My Support Groups:
Hey hk216 I don't think this thread has many eyes on it. That is a very interesting crossroad btw so you may want to move it to where it can get proper attention.
Reply

Crohn's Disease Forum » Treatment » Imuran/Azathioprine/6-MP » Questioning An Azathioprine Withdrawal Study
Thread Tools


All times are GMT -5. The time now is 05:31 PM.
Copyright 2006-2017 Crohnsforum.com