152. Atypical Drug Trials, SGLT2, Frozen Shoulder, Physical Therapy

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2771670

trials are not real life. We know that. Realistically if your drug just barely hits 0.05 in a clinical trial then in the imperfect setting of the clinic of every day life the drug likely wont work. In this next study, in jama internal medicine titled
Concordance Between Blood Pressure in the Systolic Blood Pressure Intervention Trial and in Routine Clinical Practice

The authors used a prognostic study and took 3074 patients and wanted to see the difference between BPs obtained in routine clinical practice and the bp obtained during a clinical trial. Which trial you ask?? The sprint trial!!

This is brilliant they basically took 3000 patients who were in the SPRINT trial, and as a reminder the sprint trial is the land mark trial of
2015 that showed- In patients at high risk for CVD but who do not have a history of stroke or diabetes, intensive BP control (target SBP <120 mm Hg) improved CV outcomes and overall survival compared to standard therapy (target SBP 135-139 mm Hg),
And compared the blood pressure that was taken for measurement and calculation during the trial and compared it with the bp that was calculated during the normal office pcp visit outside of the trial setting. Ideally these should be the same! Right?? If you are going to the study center and getting your bp taken or you are going to your normal doctor and getting your bp taken the results should be the same. You are taking the same meds you should get the same results?!??

But they found those in the intensive arm had a SBP that was 7mm hg higher in the doctors office compared to the SBP measured in the SPRINT trial.
those in the standard of care arm had a SBP that was 5mm hg higher in the doctors office compared to the SBP measured in the SPRINT trial.
What does this mean?? It means in the doctos office we don’t measure bp the same way they do in trials. I am not sure it means more MACE but if we extrapolate from other date we can say likely an error in bp reading of 6mm hg does make a difference.
Moral of the story. Studies are far from perfect. And often we overlook the methods and jump straight to the results but if you are going ot use a trial in practice the methods is maybe one of the most important parts of the paper if you want to get the same results else you can expect you clinical results to vary from the study results just like was shown in this paper.



topically applied corticosteroids and emollients are the mainstay of therapy for atopic dermatitis or that is at least the opening line on uptodate

but what if we question medicine as done in this paper titled

The Effects of Common Over-the-Counter Moisturizers on Skin Barrier Function: A Randomized, Observer-Blind, Within-Patient, Controlled Study

https://journals.lww.com/dermatitis/Fulltext/2020/09000/The_Effects_of_Common_Over_the_Counter.7.aspx

which look sough to look a little deeper into this standard of care for atopic dermatitis.

They took 20 points and randomized them to 1 of 4 moisturizers (Cetaphil Cream, Aveeno Eczema Therapy Moisturizing Cream, CeraVe Moisturizing Cream, Vaseline) on one arm but then NO moisturizers on the other arm. The patients were acting as their control. The right arm gets treatment the left arm gets no treatment. They did this for 4 weeks and then they accessed for Transepidermal water loss (TEWL), capacitance, pH, via tape stripping of stratum corneum.

The results showed that after 4 weeks of treatment there was no significant change in pH or in Transepidermal water loss. But the treated side did show an improvement in capacitance.. so basically the arm you put moisturizer on was more ‘hydrated’…shocking.

The authors conclude “The effects of moisturizers on nonlesional AD skin were small and need to be addressed when powering future studies.” Which really means that we give moisturizers for atopic dermiatitis with almost no evidence they do anything and it is about time we run some trials to see if what we have been doing for years is actually effective. AND since really the only outcome we can change is skin hydration then your best bet for atopic dermatitis is to use something really thick and heavy like bacon fat….or Vaseline.


https://www.bmj.com/content/371/bmj.m3576


there is an old saying that goes you can lead a horse to water but you cant make them drink… but what if you could make them drink. It turns it they would do just as well or so says this article in the BMJ titled Targeting rehabilitation to improve outcomes after total knee arthroplasty in patients at risk of poor outcomes: randomised controlled trial. That took 334 patietns who had just underwent total knee arthoplasty for kneee osteoarthritis and randomized them to either six weeks of outpatient physical therapy or to a home exercise based regimen. A Self directed PT!! You meet with the PT at the start of the 6 weeks then they give you a pat on the back and say, ok, good luck scooter.
Primary outcome was Oxford knee score at 52 weeks,

You needed at least a 4 point difference to be clinically significant and in this trial there was only a 2 point difference in the oxford knee score at 52 weeks, meaning there was no clincially meaningful difference in pain and function when you looked at outpt vs in your house physical therapy. I am a big pelaton fan because I can workout from home, maybe physical therapy from home should be the next app invention—you don’t need to lead a horse to water, you can lead to them to their house all you have to do is get them to drink or in this case do physical therapy after a total knee arthroplasty.
bottom line



Filion KB et al. Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: Multi-database retrospective cohort study. BMJ 2020 Sep 23; 370:m3342. (https://doi.org/10.1136/bmj.m3342)

Findings from a large observational study are consistent with results of randomized trials.
In several randomized, controlled trials, sodium–glucose cotransporter-2 (SGLT-2) inhibitors lower major adverse cardiovascular events compared with placebo; but what about sglt2 inhibitors next to things like an active arm!!!??

in this database obsersvational study from canada and the UK they identify 200,000 pairs of adult patients — each pair contained one who started an SGLT-2 inhibitor (i.e., empagliflozin, canagliflozin, or dapagliflozin) and the other who started or continued a dipeptidyl peptidase-4 (DPP-4) inhibitor. (DPP-4 inhibitors have no known association with adverse cardiovascular outcomes.)
During mean follow-up of 9 months, major adverse cardiovascular events occurred significantly less frequently in SGLT-2 inhibitor users than in the DPP-4 inhibitor users NNT of 200.. which doesnt sound like a lot but over only 9 months that is pretty good.
Results were similar regardless of age, sex, and specific SGLT-2 inhibitor used.
This study, although limited by its observational design, was conducted with active comparators in real-world settings and adds to the evidence that the three SGLT-2 inhibitors evaluated in this study have cardioprotective effects beyond those that derive simply from improved glycemic control.


Rangan A et al. Management of adults with primary frozen shoulder in secondary care (UK FROST): A multicentre, pragmatic, three-arm, superiority randomised clinical trial. Lancet 2020 Oct 3; 396:977
Frozen shoulder is the diagnosis but what is the treatment? You can do manipulation under anesthesia or arthroscopic capsular release or you can send them to PT.
Some of you might say wait andrew you forgot about hydrodilatation—I did not- the authors of this study prior to starting the trial did a search for the treatments of frozen shoulder and they say and I quote
The evidence of the effectiveness of hydrodilatation was deemed to be inconclusive based on poor study design and limited evidence and the evidence of effectiveness to be inconclusive….
What is the best answer?? Well prior to this the largest study on frozen shoulder was
in this U.K. that randomized 500 adults to receive manipulation under anaesthesia or arthroscopic capsular release (each followed by as many as 12 sessions of PT),, or an intra-articular steroid injection followed by early structured 12 physiotherapy sessions during 12 weeks.
The primary outcome was the Oxford Shoulder Score (OSS; 0–48) at 12 months - minimum clinically important difference of 5 points in OSS when comparing early structured physiotherapy with either surgical treatment
In the end the oxford shoulder score is a 48 point scale and all groups started around 20 at baseline which is by all accounts when someone is defined as having moderate to severe shoulder arthritis and should consider seeing an orthopeadic surgeon. but upon completion they were all around 38 which is looked at upon as a place that “May indicate satisfactory joint function. May not require any formal treatment.” …. So went from bad to not really bad at all—and No clincal difference between the three arms
Take home message--- if you have a frozen shoulder walk into your office, consider steroid injection and refer to a physical therapist you trust to get them in ASAP
Blinding of participants and clinicians to treatment allocation was not possible or desirable in this pragmatic trial. Therefore, participants and clinicians were informed about treatment allocation immediately after randomization which can only help bias the intervention group… we know people that have injections or surgery think that they do better even when they get a sham surgery..placebo is real because the mind is real and powerful
The surgeries were done on a day case by case basis within 18weeks, so maybe in the 3-4 months from time to randomization you got much worse frozen shoulder which made you was worse at baseline than those in started immediately with PT.
Finally this was a pragmatic trial which is an ideal way to run this trial. Often trials comparing two arms are run as explanatory trial.. explanatory trials are great for ideal situations, this basically says ‘could this work in ideal conditions’. Where pragmatic trials are great if you want to know how trials work in real world. Pragmatic trials have less exclusion criteria so more people can be enrolled. Pragmatic trials are great at asking could this intervention work if rolled out into the real world under the conditions that are the normal in our daily lives. Drug companies often don’t like pragmatic trials but this is a great example of one and certainly something I wish we saw more often.