Thanks for sharing my post John. I have had many conversations over the years and many of us have had reservations about the drug. In the UK, NICE recommended it in 2021 for GI bleeding only (weird decision I think based on better than outcomes predicted by Rockall scores in 90 patients in ANNEXA-4).
We studied how hospitals reacted to this (https://onlinelibrary.wiley.com/doi/full/10.1002/jha2.648 )and only two that I know of actively took the decision not to stock it. My impression is that the majority of haematologists were not impressed with the data but felt like they had to have it in the hospital because it was (A) licensed and (B) NICE approved. I think there were concerns about litigation if they took the decision not to stock it.
Medicolegal concerns in these sorts of situations is a really interesting concept but not properly studied - but I am sure it drives decision making even when the evidence doesn't stack up. Whether this is misguided or not, I don't know.
This is a good example of what happens when KoLs (many of whom were emotionally invested in the trials) lead the way, write the guidelines, and this is all supported by a powerful story. It is particularly prominent when the drug in question is a specialist drug but prescribed and used by non-specialists. In that situation, the balance betwen power of story and rationale argument swings towards story because few people who are at the clinical sharp end are experts in the evidence, and prefer to give something than not give it.
My final point is to just touch on whether a proper RCT would have been doable. In short, yes, technically, but difficult. To power for a a 5% reduction in death in ICH, you'd need a trial of about 2000 patients. Given that ANNEXA-I took 4y to recruit 500, you could think it would be difficult. But this is not that uncommon a scenario - in our very large 4 hospital organisation, we're reversing about one patient a day - granted not all intracerebral haemorrhage though. Anyway, the trial would have been tough. But does that justify use of a surrogate outcome that is unproven.
I'll be doing a lot more on reversal in coming years. There are novel, specific reversal agents coming. These don't seem to have the same thrombosis signal but who knows. They need proper testing and I think we will end up being a lot more careful with them.
Many many talking points and things to reflect on.
I would be very happy to write something for you if wanted.
“A spokesperson for [AstraZeneca] told Medscape Medical News in an email that the Biologics License Application was being withdrawn for commercial reasons.”
Not because it didn’t work. (It didn’t). Not because it hurt patients. (it did).
But for “commercial reasons”.
Legal probably told them that to admit any other reasons would open them up to lawsuits.
“The story is a fascinating example of misguided ethical thinking, and the human weakness for the power of narrative.”
It seems pretty consistent that as much as we try to be data driven it’s the *story* we tell that compels our decision making.
This has been a truly remarkable and tiring year in my long practice of medicine, both navigating the ‘evidence’ and a new level of negotiation skills in the exam room like never before.
Thanks to the Sensible Medicine team for the nearly Sisyphean task that helps me refine my approach to the practice of medicine. I’m ultimately in this messy human profession for the story, but that is why I’m in primary care. I’m looking forward to a few weeks off and a happy 2026! 🥂
In critical clinical situations, such as life- threatening bleeding on DOACs, and no “ targeted” antidote , the bar for critical appraisal plummets. This is exclusive of the financial incentives. Remember, it’s not the money,It’s the MONEY.
Surrogate markers remind me of the girl that looks a lot better than yours, so you move on, then realize she was a disaster.!😁
When I was still practicing we fought hard to keep this drug from being approved at our health system for exactly the reasons you describe here. It’s a dangerous and expensive drug without proven benefit.
Alarm bells started ringing in 2015 for those listening. Vinay heard them loud and clear, proof of his loyalty to truth. I did as well (https://researchtranslation.substack.com/p/the-60000-drug-that-never-worked), calling for the drug's withdrawal years ago and again last year. Was a $60K per dose scam from the outset, cleverly couched in 'emergency' one-arm 'trial' baloney. The lesson is to never lower scientific standards—two RCTs, both double-blinded, with genuine replication, must be a bare minimum for any approval. Good thing we have Vinay at the FDA. And kudos to you all at SM for being on top of this, and trumpeting.
My husband had emergency surgery for an incarcerated hernia 2 years ago. His surgeon walked in to talk to him pre-op and said “There is a reversal drug for your Eliquis, but I’d rather not use it. I’ve had two patients stroke after receiving it. I think I can do your surgery with minimal bleeding.” My hubby said ok. Surgery went without complications.
Hubris and financial incentives sure do explain a lot. I'll bet Vinay drives a lot of people nuts, but he sure does ask good questions. Thank God for the skeptics.
Thanks for sharing my post John. I have had many conversations over the years and many of us have had reservations about the drug. In the UK, NICE recommended it in 2021 for GI bleeding only (weird decision I think based on better than outcomes predicted by Rockall scores in 90 patients in ANNEXA-4).
We studied how hospitals reacted to this (https://onlinelibrary.wiley.com/doi/full/10.1002/jha2.648 )and only two that I know of actively took the decision not to stock it. My impression is that the majority of haematologists were not impressed with the data but felt like they had to have it in the hospital because it was (A) licensed and (B) NICE approved. I think there were concerns about litigation if they took the decision not to stock it.
Medicolegal concerns in these sorts of situations is a really interesting concept but not properly studied - but I am sure it drives decision making even when the evidence doesn't stack up. Whether this is misguided or not, I don't know.
This is a good example of what happens when KoLs (many of whom were emotionally invested in the trials) lead the way, write the guidelines, and this is all supported by a powerful story. It is particularly prominent when the drug in question is a specialist drug but prescribed and used by non-specialists. In that situation, the balance betwen power of story and rationale argument swings towards story because few people who are at the clinical sharp end are experts in the evidence, and prefer to give something than not give it.
My final point is to just touch on whether a proper RCT would have been doable. In short, yes, technically, but difficult. To power for a a 5% reduction in death in ICH, you'd need a trial of about 2000 patients. Given that ANNEXA-I took 4y to recruit 500, you could think it would be difficult. But this is not that uncommon a scenario - in our very large 4 hospital organisation, we're reversing about one patient a day - granted not all intracerebral haemorrhage though. Anyway, the trial would have been tough. But does that justify use of a surrogate outcome that is unproven.
I'll be doing a lot more on reversal in coming years. There are novel, specific reversal agents coming. These don't seem to have the same thrombosis signal but who knows. They need proper testing and I think we will end up being a lot more careful with them.
Many many talking points and things to reflect on.
I would be very happy to write something for you if wanted.
“A spokesperson for [AstraZeneca] told Medscape Medical News in an email that the Biologics License Application was being withdrawn for commercial reasons.”
Not because it didn’t work. (It didn’t). Not because it hurt patients. (it did).
But for “commercial reasons”.
Legal probably told them that to admit any other reasons would open them up to lawsuits.
Another triumph of technology over reason.
This quote by Dr Buka!!
“The story is a fascinating example of misguided ethical thinking, and the human weakness for the power of narrative.”
It seems pretty consistent that as much as we try to be data driven it’s the *story* we tell that compels our decision making.
This has been a truly remarkable and tiring year in my long practice of medicine, both navigating the ‘evidence’ and a new level of negotiation skills in the exam room like never before.
Thanks to the Sensible Medicine team for the nearly Sisyphean task that helps me refine my approach to the practice of medicine. I’m ultimately in this messy human profession for the story, but that is why I’m in primary care. I’m looking forward to a few weeks off and a happy 2026! 🥂
In critical clinical situations, such as life- threatening bleeding on DOACs, and no “ targeted” antidote , the bar for critical appraisal plummets. This is exclusive of the financial incentives. Remember, it’s not the money,It’s the MONEY.
Surrogate markers remind me of the girl that looks a lot better than yours, so you move on, then realize she was a disaster.!😁
Ben Hourani MBA
When I was still practicing we fought hard to keep this drug from being approved at our health system for exactly the reasons you describe here. It’s a dangerous and expensive drug without proven benefit.
Somehow, I knew it was a s*** drug. As a hematologist, it just smelled wrong from the start. Have never used it. Have never regretted it. Period.
Thank you for your critical and sensible approach to medicine. Looking forward to more in 2026.
Alarm bells started ringing in 2015 for those listening. Vinay heard them loud and clear, proof of his loyalty to truth. I did as well (https://researchtranslation.substack.com/p/the-60000-drug-that-never-worked), calling for the drug's withdrawal years ago and again last year. Was a $60K per dose scam from the outset, cleverly couched in 'emergency' one-arm 'trial' baloney. The lesson is to never lower scientific standards—two RCTs, both double-blinded, with genuine replication, must be a bare minimum for any approval. Good thing we have Vinay at the FDA. And kudos to you all at SM for being on top of this, and trumpeting.
Yay Vinay✅
My husband had emergency surgery for an incarcerated hernia 2 years ago. His surgeon walked in to talk to him pre-op and said “There is a reversal drug for your Eliquis, but I’d rather not use it. I’ve had two patients stroke after receiving it. I think I can do your surgery with minimal bleeding.” My hubby said ok. Surgery went without complications.
This podcast name surely is spot on. Where was the "sensibility" applied when this med was allowed?
Thank you for all that you do. Looking forward to SM in 2026.
Surrogate endpoints!!!!! Not everything that sounds like a good idea turns out to be a good idea.
Treat patients, not tests (including mechanisms of action).
Net benefit is what counts. Not benefit while minimizing/ignoring the harms.
The 'misguided ethics' is really a smokescreen to gain approval for a poor product.
Beyond shameful. It was another reprehensible Big Pharma-derived pillaging of the public purse.
Hubris and financial incentives sure do explain a lot. I'll bet Vinay drives a lot of people nuts, but he sure does ask good questions. Thank God for the skeptics.