We've already published why the published trials on combination therapy are fatally flawed and not worth the paper they are written on. But here they come again: garbage in, garbage out!
A Systematic Review and Meta-analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism
Amit Akirov, Rouhi Fazelzad, Shereen Ezzat, Lehana Thabane and Anna M. Sawka
Princess Margaret Cancer Centre, University Health Network, Canada
McMaster University, Canada
University Health Network (UHN), Canada
University of Toronto, Canada
Background: The standard of care in management of hypothyroidism is treatment with levothyroxine (L-T4). Sometimes patients are dissatisfied with L-T4 and the combination of levo-triiodothyronine (L-T3) with L-T4 is considered.
Methods: We performed a systematic review and meta-analysis of blinded randomized controlled trials (RCTs), reporting how often hypothyroid patients prefer combination L-T3/L-T4 treatment to L-T4 alone. We also explored for explanatory factors for combination therapy preference in sensitivity analyses examining trial, patient, and disease characteristics. Potential dose-response relationships were explored using meta-regression analyses. We searched 9 electronic databases (from inception until February, 2019), supplemented with a hand-search. Two reviewers independently screened abstracts and citations and reviewed full-text papers, with consensus achieved on the included studies. Two reviewers independently critically appraised the quality of included studies and abstracted the data. Random effects meta-analyses were reported for the percentage of patients preferring combination L-T3/T-T4 therapy over L-T4 alone. A binomial distribution of choices (i.e. preference of combination therapy or no preference for combination therapy) was assumed.
Results: We included 7 blinded RCTs including 348 hypothyroid individuals in the primary meta-analysis. The pooled prevalence rate for preference of combination therapy over L-T4 was 46.2% (95% confidence interval 40.2%, 52.4%) (p=0.231 for the difference from chance). There was no significant statistical heterogeneity among study results (Q = 7.32, degrees of freedom = 6, p = 0.293, I2 = 18.0%). In sensitivity analyses, combination treatment preference was explained in part by treatment effects on TSH concentration, mood and symptoms, but not quality of life nor body weight. In a secondary dose-response meta-regression analyses, a statistically significant association of treatment preference was identified for total daily L-T3 dose, but not L-T3:L-T4 dose ratio.
Conclusions: In conclusion, in RCTs in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination L-T3 and L-T4 therapy compared to L-T4 alone; this finding was not distinguishable from chance. An observed potential positive L-T3 dose effect on treatment preference deserves further study, with careful consideration of thyroid biochemical indices and patient reported outcomes.
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diogenes
Remembering
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Thank you Diogenes. How depressing. I wanted to ask you about something. I saw a new GP the other day, didnt like him much, he was very negative about my taking thyroid hormones and told me to stop. I thought that I might tell him that I will stop my thyroid hormones if he can find some reasurch that demonstrates that the TSH is a consistently reliable diagnostic tool and that the range of normality suggested in the uk is consistant with good health. Before I make such a suggestion I would like to be confident that he does not stand a chance. Do you know that that would be the case?
Thank you Diogenes but if I take him in some paper work he will just ignore. I am trying to challenge him to back his understanding and advice re the tsh being 'gold standard' and my not being hypothyroid. I am imagiing that if he does try to find anything he will find alsorts of recent studys, like the one above but I presume there must have been some scientific evidience at one time for it to be used so widely or was it all a big con in the first place. I might have to add the cavetate 'in the last 20 years'.
If he tries to ignore it, just point to a basic scientific prinicple: that a hypothesis needs only one good paper to test it and disprove it for the hypothesis to fail. The TSH hypothesis - and this is all it ever was - has failed. The now-numerous meta-analyses of the same old, statistically flawed papers to 'prove' that TSH is king, are just so much recycled junk.
right so I need to be able to refute his papers. I think I will just sack him and find someone else. t is no good tryinto educate doctors. You can only take a horse to water etc. Thye have learning difficaultys which mean they are unable to engage and process what people tell them, unless it comes from another doctor or maybe a drug rep.
The whole meta analysis concept is flawed by design. Look at a lot of studies that might or might not have been well-conducted or worthwhile and then "average" them, leaving out the bits you don't like, instead of doing "proper research" - cheaper, yes; useful, hmmmm.
The idea that T4 therapy is just the same as the healthy thyroid's production, and that therefore TSH will respond in the same way in health and disease is just that, an unproven idea. It is actually wrong. The thyroid produces T3 as well as T4, and when the thyroid is lost, that T3 production is also lost. If you now give T4 only, the body's conversion has to both achieve its natural working + also having to make up for the T3 the thyroid was making. Therefore to get to the same T3 as you had when well, you have to take more T4. This suppresses the TSH often below the healthy range .It is more important to normalise your FT3 than try to normalise TSH.
Dear Diogenes, do you know if there is any recent research evidence regarding the overlooked significance and value of rT3/T3 ratio results? For instance, could poor conversion ever be attributed to elevated inactive rT3 taking active T3's place at cellular level - rather than, or as well as, other reasons, such as DIO2 polymorphisms. If a patient's rT3 ratio is low can this be a useful marker to pursue with endocrinologist who solely relies on evaluating TSH, not the bigger picture. Example: Reverse T3 Ratio 12.46 [15.01-75.00] I am ever grateful for your comments and research.
rT3 and T3 react differently with receptors specific for each one. rT3 can be useful in determining conversion efficiency and could confirm it as a high result if the FT4/FT3 ratio is high on T4 only. I don't think they compete strongly for their cell actions, but there may be some special reactions which rT3 promotes.
Originally, an endocrinologist explained the body 'dumps' rT3 and it is of little use. However, can it be the case rT3 binds to T3 receptors blocking the action of T3. If rT3 domination occurs would hypothyroid symptoms result if T3 and T4 remained 'in range?'
No, that can't happen: rT3 and T3 have different receptors and can't steal each others. It just means that T4 is converted to more rT3 and less T3 than usual, so you have less T3 for use by cells. Both eventually get converted to T2. We don't really know what else rT3 does. "In range" means nothing. You need the optimal level for you as an individual and that varies enormously
Out of curiosity and with your academic background, how would a study like this be funded, diogenes? There almost seems to be a desire to regurgitate that there’s no proof a combination therapy works, like you say, despite evidence to the contrary.
Interestingly, I added liothyronine without reducing Levo so in my case the substitution of 1:4 does not seem to work, same must be true for many others.
There are so many variables to thyroid care that putting everyone on the same dose regeime is hardly going to get statistically good results. Also the 50% mentioned as chance when we are talking about a small percentage of people who benefit anyway is silly. I have never heard of the placebo effect as chance before and I am sure that antidepressants etc have been promoted on a lesser percentage.
I think the folks at McMaster have a political agenda - am I mistaken, or is one of the authors on the subclinical hypo study from there also? Plus, meta analyses have methodological problems depending on selection of studies to include. Don’t like what I am seeing coming from there and find it worrisome when newer original research suggests otherwise.
I agree it's particularly worrying given what is happening in Canadian thyroid care, and the ban on FT3 testing in the public medical system. This absurd meta-analysis may well be scientific cover for a set of public policy decisions.
My thoughts exactly. I had posted some time ago about the fact that my hospital will no longer test for T3 unless an endo asks for it. There is some academic/policy group pushing this agenda, not sure what’s in it for them. And the tie in with the British study makes it even more worrisome - they are communicating across the pond with this nonsense.
Do you think they are pumping money into this sort of review after review to be able to use it to support what is happening now, i.e the systematic withdrawal of T3? To boost the 'subject matter' supporting t4 mono and TSH testing? A sort of 'our pile of (crap) evidence is bigger than your pile of evidence?
What doesn’t make sense to me is that Pfizer manufactures Cytomel in Canada - big pharma company equal to the manufacturer of Synthroid. So I can’t see big pharma really being worried about that. Patients who have issues will be on both T4 and T3 anyway so both companies will make money all the same.
I think there is someone in academia who has staked their career and reputation on this notion of TSH and T4 - and they have decided to really push it. And, they may have convinced some policy wonk in the govt go along with this nonsense.
And BTW - meta analyses are cheap to do - you get grad students to do the heavy lifting of the statistical analysis. You don’t need a big grant for that. You don’t even need original data - you are using other people’s data! And everybody and his brother gets on the paper and the credit too. 😉
I have said for several years now, there is a 'Boys Club' [well, there's many of those about ] determined to continue driving through their 'little pet theories' at any and all cost to patients. Some of these have held or hold reasonably elevated positions... they will not stop, until someone or a group [metaphorically] takes them down via their outrageous garbage, damaging so many lives.
Also take a look at some of the papers written by Dr John Lowe (shaws often provides links) - he sent to whichever UK 'big shots' - only to be ignored out of hand by the arrogant, ignorant establishment. The treatment of hypothyroidism will surely, one day, go down as one of the biggest medical scandals... especially given its rich history. I do hope I'm still alive when that happens... not hopeful though
Sound scientific method relies on falsifiability, and the TSH hypothesis needed to be tested and found wanting only once. Once. If medical science were real a science, we would all have moved on long ago. But in this field the 'weight of evidence' people seem to hold sway, and not only in thyroid testing and treatment. Whatever is going on, it ain't science.
If I hear the words “evidence based care” uttered by an MD or medical researcher again, I will rip out the little hair I have left on my head. What evidence? Whose evidence? Who decided it was good evidence?
Not to mention that the evidence is changing constantly. Example — HRT ( sorry no thyroid example). First, evidence says take them like aspirin. Then, no it causes cancer. Then, no, it’s good for the heart. Then, no it can cause increased risk of stroke. Then, it protects the memory. After that, well we are not sure. Now - it’s 5 years use maximum till the age of 60 at the lowest dose. So when will that “evidence” change again?
This raises another question. Why is the field of endocrinology not moving with respect to revised evidence (the hated word) ? For example, my thyroid surgeon told me that almost no one wants to research Graves anymore because cancer is a more publishable topic. He is a specialist in thyroid and specifically on Graves. Endocrine research on the thyroid is not sexy, folks. And that’s all she wrote.
Well, to all of you on this amazing forum, sorry for the ranting today, but this article really got to me and so I am abandoning my usual balanced demeanour to let out an uncharacteristic 😱 scream!
And thanks to diogenes and the post. Plus the wonderful quote by Cromwell of course. Have a good night, from me - across the pond.
Scientific published 'research' largely seem to benefit those paying for said research IMHO. And those funding the research quite often seem to benefit financially from it at some point further down the line.
Cigarettes being good for you springs to mind. Until people started dropping like flies and we 'discovered' they weren't so good for us after all.
Don't get me started on medical cannabis! Studies show it is dangerous and has no medical value - according to various governments (the last person to state such a bald-faced lie on the subject being David Cameron). If that statement were true, one has to wonder why the UK is the biggest grower and exporter of medical cannabis in the world...
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] determined to continue driving through their 'little pet theories' at any and all cost to patients. Some of these have held or hold reasonably elevated positions... they will not stop, until someone or a group [metaphorically] takes them down via their outrageous garbage, damaging so many lives. 
