The real issue is not knowing how many subgroups were prespecified.
If they prespecified 20 different subgroups based on different CRP cutoffs, statistically one of those will be found to be incorrectly significant.
I never said it wasn't interesting. What I did say is it doesn't make sense. It needs additional studies before the FDA approved an extremely invasive procedure without a clear mechanism with an experimental group of cells that failed to meet the primary endpoint.
If the cells work and can have that effect, it'll be great, and I guarantee I'll be prescribing them at some stage.
I'm just far from convinced that they work.
I'll give them the benefit of the doubt - that a CRP above 2 is significant.
So let's make it binary, we have people with inflammation, and people without (this is not necessarily a statement I agree with at these cutoffs, but for arguments sake here we go).
You have a cohort with inflammation. From somewhere. And they have heart failure, from any number of causes. Why does an injection of a transient population of cells into the muscle tissue of the heart, theoretically lowering inflammation, reduce the likelihood of heart attack and stroke long term?
Is that inflammation coming from the myocardium itself? Are the cells decreasing inflammation in the myocardium, stabilising any plaques in the coronaries? If that's the mechanism, that's interesting because traditional anti inflammatories can make heart failure worse, steroids don't help. And the coronaries are better accessed via systemic circulation.
Really it depends on what type of heart attack we are looking at - We looking at preventing sudden plaque rupture causing a big Ol' STEMI, by stabilising the plaques in the coronaries (inflammation is thought to increase risk of heart attacks through this mechanism, among others). Is this preventing type 2 MI, or demand driven ischaemia? This is due to more stable narrowing, and rather than the supply of oxygen suddenly decreasing to the heart, the requirement increases and the body can't keep up (stable narrowing of the coronaries, hypoxia, anaemia, hypotension, etc). I'm guessing this would be less effected.
But if it's the big STEMI from plaque rupture - a systemic infusion would be better, no? Maybe the cells would get filtered by the lungs and stuck on their way to the coronaries, but that's not an issue when looking at aGVHD. Maybe they should look at infusing the cells into the coronaries, as they infuse dye during an angio.
Now, is the inflammation coming from somewhere in the body and the coronary vessels are being affected? If so, why is a systemic infusion of these cells not more effective? Less invasive? That would be an interesting study.
Don't forget, CRP isn't inflammation. It's a marker for inflammation, it's an acute phase reactant. It's not hanging out at one level in patients,
If you do a CRP on one individual, and do it again 3 hours later (even if they don't have an infection that is dynamic) it will be a different number - not clinically different, maybe 7 instead of 2. But both those numbers are a "non-elevated" CRP. Don't believe me, that's fine, but I've seen this many times first hand, hence why I'm skeptical about all of this.
CRP lags, a high CRP indicates inflammation that was there 12, 24 hours ago, but may not be there now. Its an indirect marker of inflammation.
Its interesting stuff. I know you've always said you don't think they'll get accelerated approval so I'm preaching to the choir, I'm sure. Because what I'm saying is the data doesn't actually make much sense if you understand the industry, and will absolutely need a further trial to confirm results - that's all I've ever said, and I constantly beat the drum about it because of the nonsense you see above about buying boats later this year when CHF indication comes through.
Its misleading, and extremely unlikely. IMO
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