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1. Why is intention-to-treat the ONLY right way to interpret trial results?
2. Why are these fine gentlemen wasting their prayers?
Tweetorial for cardiology fellows from ORBITA-HQ
#cardiology #meded #foamed
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But Pascal Meier insisted that it was.
He said he was watching a whole session dedicated to not understanding this at a conference. Sent a pic!
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We have noted the immortal words of Prof T Luscher, and have followed his suggestion for focus.
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Reaching the stem cell lab, it's really worth it - look at all this sciency stuff!
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Highly statistically significant, p<0.0001
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The all cause mortality rates are 61% in the control arm and 5% in the active arm.
What is the ABSOLUTE risk reduction?
(In absolute percentage points)
What is the NNT? [Can do without a calculator]
Hint: it is 1/ARR. If expressing ARR in absolute percentage points, it is:
100 / (ARR in absolute percentage points)
How about as a RELATIVE risk reduction?
Again do this without a calculator. Get a very rough idea and pick the one that is closest to it. I am telling you in advance that ONE of these is correct.
Please collect your checks in the foyer.
Our CEO uses your support to get it through the FDA.
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They asked, "Did you really make your patients with cardiogenic shock walk up all those stairs?"
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"What happened to the patients who didn't make it up the stairs to get the stem cells?"
Our lawyers replied,
"They were protocol violators and were excluded from the study."
How did the FDA reply?
No, the FDA would want everyone included.
So our weary statistician spends another all-nighter re-cooking the books.
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Each wants to be the one to give out the good news!
Here it is, p still less than 0.001! Nobody had to be deleted!
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71% in the control arm
5% in the active arm
What is the absolute risk reduction? (in absolute percentage points)
One of these numbers is correct. In your head, you should be able to see that ONLY ONE is plausible: pick that one.
There are very simple tricks to do it but I am assuming people know them if they aren't asking.
These people are very, very good at math and logic.
All except the boss, who is a bit zany:
[Oddly in the thread here, the correct answer, B, was only picked by one out of 7.]
What do you think they immediately recognised was strange?
What has the FIDDLE-1 steering committee NOW done with the protocol violators?
Randomized to active Rx, but collapsed on the way up the stairs. Some had died and tumbled down. Others begged to be taken back down, and died later. A few survived.
"Some ungrateful wretches didn't even have the courtesy to show up for their very expensive treatment, given FREE, gratis and for nothing, by our illustrious corporation.
At first we excluded these parole violators..."
This is CLEARLY the best way to examine device trial data. How can you benefit from a device if you don't get the device? Ridiculous nonsense spread by the likes of F2Harrell: ivory tower do-gooders."
Even the parole violators! Hmph.
So we did. Obviously they didn't get the stem cells, so they are controls, yes?
This is the well known 'AS TREATED' analysis."
PER PROTOCOL, 92% RRR, p<0.001
AS TREATED, 93% RRR, p<0.001
We pay taxes that provide your salaries, you FDA nobodies.
Shut up and give us our licence or we will call our friend Scott Gottlieb."
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Using the width of the confidence intervals, we back-calculated the numbers of patients ANALYSED in each arm [Another weekend we will study how to do that for fun and profit]
First the first presented analysis, DELETING THE PROTOCOL VIOLATORS.
The PER PROTOCOL analysis.
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This is the "AS TREATED" analysis.
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Or shall I take you through it?
Seeing either, is an immediate warning sign: "COME HERE TO BE CONNED".
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The difference between PER-PROTOCOL and AS-TREATED is that in one you DELETE people who collapsed on the stairs, and in the other other you PUT THEM INTO THE CONTROL arm.
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Hint: it is the difference between these two numbers
(For an ITT analysis)
So how many ACTIVE arm patients should there be in the ITT analysis?
HINT.
Both naughty analyses (per protocol and as treated) listed 300 pts in the active arm. Those made it all the way up the stairs.
There were another 700 active arm patients who didn't.
How many active arm altogether?
MEGA HINT.
300+700=what?
So we can fill in the NUMBERS OF PATIENTS for the ITT analysis, as shown below.
How about the numbers of DEATHS?
How many DEATHS were shunted into the control arm when the FDA said not to delete them?
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HINT.
Round the numbers to the nearest 100...
How many active arm deaths are there in total, in the ITT analysis?
The number you just said, plus the 15 we admitted to earlier.
I use the authority given to me by the statin denialists to ignore this fact and carry on quoting it, regardless.
It has a certain "truthiness", even if untrue
Here it is!
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Per-protocol and As-treated are two different types of pin: don't let them near your reading of a trial, however persuasive the sales patter.
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There are more subtle ways.
If they don't do it, due to unfortunately dying in the first 7 days, they are parole violators. Delete them (or, for maximum fun, put into the "enemy" arm).
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Bonus marks if we can shove them into the control arm - "as treated" analysis.
What is the point of randomization, if the investigator (sometimes directly, sometimes by biasing the patient's choices) can move a patient into any arm at will?
You are advising future patients at this juncture that DECIDING to have (say) an angio is a good idea, or not.
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Or still in the CABG arm, even if the patient or surgeon decided in the end not to do it.
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Or still in the ezetimibe arm, even if they stopped taking their blinded medication.
Yes, ITT deflates the apparent benefit of the actual intervention but
(a) It is VITAL to prevent massive manipulation of RCT results
(b) In its defence, it reflects the effect of the DECISION to intervene.
[Sorry I didn't cover the relevance to the panel recommending complete revasc. I realise it is not obvious so will cover another weekend]
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However, this requires a lot of brainwork, and trust in the investigators.
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For example, about half of patients assigned to screening don't show up for it.
In real life, we could double-book people and hope only half show up (you can tell I work in the UK NHS, can't you!)
But there are subtleties (read paper, explains well). NOT just "shove them into Control arm if they didn't bother to show up."
e.g. They may be less interested in their health and therefore do worse.
E.g. Collapsed on the way to getting Stairway to Stem Cells.
Or Died waiting for LaserElectroDenervatisation.
Like James Bond finding Dr Dastardly has planted a bomb in his car. Instead of just throwing it out (Per-protocol) he actually throws it into Dr Dastardly's car (As-treated).
As-treated lets them show up, but in your enemy arm's data.
Either way, the very fact that either of these shady analyses are in a manuscript is a red flag.
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But the IMPROVE-IT dudes _knew_ they would have to analyse ITT, so they encouraged persistence but couldn't do it in a biased way.
To stop the temptation to do that, we insist on ITT.
Yes, it deflates the effect size. Tough.
Give a realistic estimate.
Likewise we insist on ITT because otherwise OCCASIONALLY someone will totally con us.
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Albert Einstein
Some RCT active-arm patients never get their pacemaker, CABG or simply don't take their meds (either secretly or by withdrawing from active participation).
Tough! That happens in real life too.
Two reasons to stand by the ITT.
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An RCT informs us the benefit of deciding "OK let's take path X".
Here Path X =
Wait for slot
Do the op
Followup Rx etc.
If that is still the path in real life, then the RCT is CORRECTLY advising on the benefit of the Path X. Yes, you might get a stroke before the device.
If you allow Francis Industries to remove that patient from analysis, then in other trials, of more acute conditions (e.g. STEMI, new onset AF) it will have a prolonged pre-procedure preparation period to flush out and delete as many events as possible.
Per Protocol
Adjustment for selected baseline variables (but not others)
etc
And then a rather dramatic claim in the abstract conclusion that this is the new standard of care.
ruptured aortic aneurysm
Or (Sergio Pinski):
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In a noninferiorty trial (medpagetoday.com/publichealthpo…) the sponsor's aim is to show NO difference, so they will love the ITT if very many people are parole violators, so both arms are getting almost the same treatment.
But there is no good way to confidently calculate the true treatment effect then.
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INTENTION TO TREAT =
Randomize once, no cheating afterwards, whatever you or the patient choose to do, whatever happens to the patient, global warming, whatever ...
DELETE some people who didn't make it through the protocol (through choice or through unhappy events such as death)
This is "Per Protocol"
Don't just delete them from their randomized arm, actually STICK THEM INTO THE OTHER ARM.
So their terrible outcomes poison your enemy's arm.
This is "As treated"
I have a trial DUFF-1 of the efficacy of a new treatment.
It shows an absolute risk reduction of 12 percentage points on Intention to Treat.
p=0.07 unfortunately.
p=0.0542
Hmmm...
Lady from Francis Industries advises "let's just call it p=0.05, see if the reviewers notice?"
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Will that make the absolute risk reduction...