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2/ I was commuting to work the other day when I read the results of the EXTEND trial nejm.org/doi/full/10.10…
EXTEND was stopped early after WAKE-UP was published due to “lack of clinical equipoise.”
Interesting. Let’s read WAKE-UP then, I thought.
EXTEND was stopped early after WAKE-UP was published due to “lack of clinical equipoise.”
Interesting. Let’s read WAKE-UP then, I thought.
3/ Here’s the link to WAKE-UP: nejm.org/doi/full/10.10…
Traditionally, systemic tPA has been reserved for patients with ischemic stroke who can be confirmed to have had onset of symptoms within the last 4.5 hours.
Traditionally, systemic tPA has been reserved for patients with ischemic stroke who can be confirmed to have had onset of symptoms within the last 4.5 hours.
4/ WAKE-UP enrolled patients who - shocker - *woke up* with new stroke symptoms. They used MRI to find patients who were likely in the traditional 4.5 hour window and randomized them to tPA or placebo.
Their primary outcome was a 0 or 1 on the modified Rankin scale at 90 days.
Their primary outcome was a 0 or 1 on the modified Rankin scale at 90 days.
5/ Results are in the table below. The NNT is ~ 9, p=0.02.
Interestingly, WAKE-UP failed to meet enrollment goals and was stopped early after funding ran dry. As a result, it was underpowered to detect a difference in mortality.
Interestingly, WAKE-UP failed to meet enrollment goals and was stopped early after funding ran dry. As a result, it was underpowered to detect a difference in mortality.
6/ 10/254 (4.1%) died w/ tPA, while 3/249 (1.2%) died w/ placebo. That yields an OR of dying at 90 days w/ tPA of 3.38; 95% CI, 0.92 to 12.52; P=0.07. If only they had enrolled more pts!
These results are published, and EXTEND stops enrolling patients. What was EXTEND studying?
These results are published, and EXTEND stops enrolling patients. What was EXTEND studying?
7/ Can the 4.5-hour tPA window be *extended* to 9 hours?
To investigate this, they enrolled people who were 4.5-9 hours from symptom onset, or who woke up with symptoms and the midpoint of their sleep was within 9 hours.
To investigate this, they enrolled people who were 4.5-9 hours from symptom onset, or who woke up with symptoms and the midpoint of their sleep was within 9 hours.
8/ They were randomized to tPA or placebo if CT or MRI perfusion scans showed evidence of “hypoperfused but salvageable regions of 🧠.”
Was this what WAKE-UP studied? No! Should the results of WAKE-UP ever affect EXTEND? No!
And yet. 😑 #crazypills
Was this what WAKE-UP studied? No! Should the results of WAKE-UP ever affect EXTEND? No!
And yet. 😑 #crazypills
9/ So what did EXTEND find? They had the same primary outcome as WAKE-UP. Data are in the table below. The NNT is ~17, p=0.04.
We know that trials ended early overestimate the benefit of intervention, and here we have a moderate NNT with a p value hanging on for dear life.
We know that trials ended early overestimate the benefit of intervention, and here we have a moderate NNT with a p value hanging on for dear life.
10/ There is also the safety question which EXTEND was underpowered to answer, similar to WAKE-UP. Symptomatic ICH was found in 7/113 with tPA and 1/112 with placebo, OR 7.75, 95% CI 0.93-64.95, p=0.059.
11/ I’m not terribly impressed with these data. One study stops early with a worrying question mark re: increase in mortality. This inappropriately leads to the premature closure of another trial which shows possible improvement and again leaves a safety question unanswered.
12/ Here I am, 🤔, hmm interesting reading. Boy, research is tough. Thanks go out to the many many researchers involved (seriously, how many authors are there?) as well as NEJM.
I go back to my life. A couple of days pass, and then I stumble across this...
I go back to my life. A couple of days pass, and then I stumble across this...
14/ Shattered? I’m squinting at the window trying to figure out if what I’m seeing is a hairline fracture or just a strand of my wife’s hair pasted to the pane of glass. I need more data before I draw a conclusion.
15/ To be fair, the editorial is more appropriately guarded at times. It points out the inequivalency of WAKE-UP and EXTEND and notes that these results must be validated with further RCTs.
But even after saying that, it again says an important barrier has been *shattered!*
But even after saying that, it again says an important barrier has been *shattered!*
16/ This is not practice-changing knowledge. This is hypothesis generating data that demands further investigation.
What worries me is that with headlines like “shattered tPA window” that folks may consider changing their practice.
What worries me is that with headlines like “shattered tPA window” that folks may consider changing their practice.
17/ Or that this data will change practice while we wait for the appropriately powered study to be performed. That study may very well be negative, and extension of the tPA time window becomes yet another exhibit in the Hall of Medical Reversal.
cc: @VPrasadMDMPH @adamcifu
cc: @VPrasadMDMPH @adamcifu
18/ What do you think?
Am I misinterpreting the data?
Are my worries overstated?
Will these trials change your practice or practice at your shop?
Am I misinterpreting the data?
Are my worries overstated?
Will these trials change your practice or practice at your shop?
