This was such an important (and humbling) case study in how good stories can outrun good evidence. As clinicians, we all felt the visceral logic: “If someone is bleeding on a factor Xa inhibitor, give the antidote”. And mechanistically, andexanet did what it was supposed to do (lower anti–factor Xa activity). But the uncomfortable lesson you lay out is the one we keep re-learning: a surrogate that moves beautifully in a lab does not automatically translate into patient-centered benefit, especially when the pivotal evidence base is single-arm, highly selected, and confounded by everything that happens in real-world hemorrhage care.
Two things really stick with me:
1. Narrative bias + accelerated approval is a combustible mix. Once a drug is “approved”, it becomes psychologically (and medicolegally) hard for hospitals and clinicians to not stock it, even if the outcome data are thin and the harms (thrombosis signal, costs, workflow burden) are real.
2. The ethical tension is real: “doing something” feels compassionate, but false certainty is not compassion. If we’re spending $20k+ per dose, we owe patients randomized outcome data, not just mechanistic reassurance.
Thank you for writing this with integrity. It’s not anti-innovation, it’s pro–scientific humility and pro–patient safety!
Thx for this discussion. As a former vascular surgeon reversing factor Xa inhibitors was crucial in the case of a ruptured AAA. I recall thinking the price tag was outrageous.
Maybe PCC will find place now in Noac reversal. I tried to look in to trial literature and FDA documents, but apparently there was no sensitivity analyses done for use or PCC.
Transparency and common sense could be making a return. But how do we stop the next set of so called experts from again espousing " the house is on fire", "doing something is better than nothing" mentality? Thanks again to the author for pointing out the truth.
This again highlights how well (or not well) the FDA of recent years has been discharging its fiduciary duty as a gatekeeper.
Some of these approval loopholes need to be closed. Or at least made to be strictly conditional on the provision of properly powered outcome study evidence as proof of meaningful benefit, rather than reliance on mechanisms and surrogate endpoints.
Sometimes it helps to go back to first principles. The market for reversal drugs for anticoagulants is likely driven by the large numbers of people being placed on anticoagulants to begin with. Whereas anticoagulants may be useful in acute cardiovascular disorders (such as acute MI or thrombotic stroke), the overwhelming majority are prescribed as preventive treatment for future acute CV disorders or to prevent recurrence of past events. The studies cited to justify the preventive use generally show a very small difference in the endpoints examined and that difference is commonly overridden by the incidence of bleeding or other complications. Some might say that "preventive" use of anticoagulants is likely to do more harm than good.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is administering T3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine because NO DOCTOR EVER MENTIONS THIS.
And worse than this, patients are given T4 ONLY, which makes atrial fibrillation a thing. So AF is often iatragenic, doctors themselves causing it because they are too ignorant to prescribe T3.
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is adnT3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine.
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is adnT3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine.
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
Recent studies have focused on the association between thyroid function within normal range and cardiovascular diseases, especially on free triiodothyronine (FT3) levels. This study aims to evaluate the effects of normal FT3 level on new-onset atrial fibrillation (AF) in patients with surgical coronary revascularization.
Methods
The patients who underwent surgical coronary revascularization were enrolled in the retrospective study. Thyroid function was tested after an overnight fast on the first morning of hospitalization. Serum FT3 level was divided into quartile groups within the normal range. Hazards ratios (HRs) of FT3 level for AF were analyzed by COX proportional hazard model.
Results
This study included 503 patients with a mean [standard deviation (SD)] age of 63 (±9) years, and 396 (78.73%) were male. Post-operative AF (POAF) occurred in 120 (23.86%) patients at a median of two days after surgical coronary revascularization. The cumulating incidence of AF was significantly higher in the FT3 quartile 1 (Q1) group especially in older patients as evidenced by Kaplan-Meier analysis. Additionally, the patients who experienced AF had longer hospital stays, the same result was also found in the FT3 Q1 group. Further study demonstrated that low-normal FT3 was an independent predictor of POAF [HR =1.52, 95% confidence interval (CI): 1.01, 2.28, P=0.045].
Conclusions
Low-normal FT3 is associated with an increased risk of POAF and is an independent predictor of POAF. Patients who experienced AF have longer hospital stays. The findings may help to identify patients with surgical coronary revascularization at a higher risk for the development of AF.
There are numerous studies linking high T4, and rT3 to atrial fibrillation. I haven’t met a Western doctor yet who prescribes T3. I only see patients who get T4, so they end up with exactly this problem — high T4 and high rT3 and are set up, by their doctors, for A fib.
Nobody is going to do a study showing that doctors are idiots. But there it is.
You don’t need to do a study to prove that doctors are idiots.
But you do need to do studies that prove whatever nonsense it is that you’re claiming with regards to T3 supplementation. Otherwise, believing in that makes you the idiot.
Could some type of companion diagnostic to better know which way the scales will tip…not a hematologist but is it about dosage of the anti- then the dosage of reversal?
I am not actually qualified to respond so please take with a grain of salt. I think the answer is yes, sometimes. If a new blood pressure drug reduced blood pressure substantially, perhaps that would be enough, for instance. But in general it sure would be nice to have clinically meaningful health outcomes rather than surrogate markers such as blood pressure.
Yes, when they are predictive, which some surrogates are. The Accelerated Approval approach allowing surrogates was originally introduced in 1992 to speed up drug development for HIV and it was a resounding success for that because the surrogates (CD4 count, viral load) were predictive. In oncology, the surrogates are not so good.
For me, the main factor is whether clinical endpoints can be measured in a timely fashion. If not (e.g., statin studies), then a surrogate that is proven to be highly correlated with the clinical outcome (e.g., cholesterol levels) is a reasonable endpoint for the initial approval. If there's no reason a relevant clinical endpoint can't be used, I expect the manufacturer to invest the time and money to conduct a trial adequately powered for real outcomes that matter to patients.
Having worked on apixaban from first-in-human to the pediatric extensions, I can honestly tell you that BMS never really wanted to help develop an “antidote”. The FDA wanted a reversal agent as did clinicians. I wrote the Clinical Overview for label change for Portola based on ANEXXA studies and we all felt it was a thin package to support full approval. Even then, we knew 4-factor PCC worked OK with no real thrombotic rebound. The tail wagged the dog and I’m glad this got taken off the market. For the Factor XI inhibitors being developed now, the same thing went on initially, but I think PCC and rVIIa will be the reversal strategy.
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.
This was such an important (and humbling) case study in how good stories can outrun good evidence. As clinicians, we all felt the visceral logic: “If someone is bleeding on a factor Xa inhibitor, give the antidote”. And mechanistically, andexanet did what it was supposed to do (lower anti–factor Xa activity). But the uncomfortable lesson you lay out is the one we keep re-learning: a surrogate that moves beautifully in a lab does not automatically translate into patient-centered benefit, especially when the pivotal evidence base is single-arm, highly selected, and confounded by everything that happens in real-world hemorrhage care.
Two things really stick with me:
1. Narrative bias + accelerated approval is a combustible mix. Once a drug is “approved”, it becomes psychologically (and medicolegally) hard for hospitals and clinicians to not stock it, even if the outcome data are thin and the harms (thrombosis signal, costs, workflow burden) are real.
2. The ethical tension is real: “doing something” feels compassionate, but false certainty is not compassion. If we’re spending $20k+ per dose, we owe patients randomized outcome data, not just mechanistic reassurance.
Thank you for writing this with integrity. It’s not anti-innovation, it’s pro–scientific humility and pro–patient safety!
Where is Vinay now, and what is he doing? He is sorely needed. Thank God for you and Adam! Stay the course.
Thanks for a great year of Sensible Medicine, John, Adam, and Andrew. This substack is brimming with integrity and critical thinking. Bravi!
Love it keep up with good work
Thx for this discussion. As a former vascular surgeon reversing factor Xa inhibitors was crucial in the case of a ruptured AAA. I recall thinking the price tag was outrageous.
Maybe PCC will find place now in Noac reversal. I tried to look in to trial literature and FDA documents, but apparently there was no sensitivity analyses done for use or PCC.
223 Andexxa Deaths from 469 case reports on US FAERS to 20 December 2025.
Transparency and common sense could be making a return. But how do we stop the next set of so called experts from again espousing " the house is on fire", "doing something is better than nothing" mentality? Thanks again to the author for pointing out the truth.
This again highlights how well (or not well) the FDA of recent years has been discharging its fiduciary duty as a gatekeeper.
Some of these approval loopholes need to be closed. Or at least made to be strictly conditional on the provision of properly powered outcome study evidence as proof of meaningful benefit, rather than reliance on mechanisms and surrogate endpoints.
Sometimes it helps to go back to first principles. The market for reversal drugs for anticoagulants is likely driven by the large numbers of people being placed on anticoagulants to begin with. Whereas anticoagulants may be useful in acute cardiovascular disorders (such as acute MI or thrombotic stroke), the overwhelming majority are prescribed as preventive treatment for future acute CV disorders or to prevent recurrence of past events. The studies cited to justify the preventive use generally show a very small difference in the endpoints examined and that difference is commonly overridden by the incidence of bleeding or other complications. Some might say that "preventive" use of anticoagulants is likely to do more harm than good.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is administering T3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine because NO DOCTOR EVER MENTIONS THIS.
And worse than this, patients are given T4 ONLY, which makes atrial fibrillation a thing. So AF is often iatragenic, doctors themselves causing it because they are too ignorant to prescribe T3.
It’s really a travesty.
https://pubmed.ncbi.nlm.nih.gov/8633935/
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is adnT3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine.
https://pubmed.ncbi.nlm.nih.gov/8633935/
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
The big blind spot is that AF is a thyroid disorder, coinciding often with higher than normal T4 and lower than normal T3, and/or high rT3. There are numerous studies showing this, and yet nobody bothers taking temperatures of the patient and giving them a good T3 supplement. That is a medical crime, that you can add to statins to lower cholesterol and many many others.
“Thyroid” in stupid medicine is considered to be T4, but in truth, thyroid is more than that, and conversion of T4 to T3 can be the main problem. Thyroid is really a mix of T4 and T3, or just T3.
Having too much T4 increases AF probability.
Is adnT3 the entire answer? Probably not. But is it a big part of the solution? Undoubtedly. I get so tired of these terrible blind spots in medicine.
https://pubmed.ncbi.nlm.nih.gov/8633935/
Background: Cardiopulmonary bypass results in a euthyroid sick state, and recent evidence suggests that perioperative triiodothyronine (T3) supplementation may have hemodynamic benefits. In light of the known effects of thyroid hormone on atrial electrophysiology, we investigated the effects of perioperative T3 supplementation on the incidence of postoperative arrhythmias.
Methods: One hundred forty-two patients with depressed left ventricular function (ejection fraction < 0.40) undergoing coronary artery bypass grafting were randomized to either T3 or placebo treatment groups in a prospective, double-blind fashion. Triiodothyronine was administered as a 0.8 micrograms/kg intravenous bolus at the time of aortic cross-clamp removal followed by an infusion of 0.113 micrograms.kg-1.h-1 for 6 hours. Patients were monitored for the development of arrhythmias during the first 5 postoperative days.
Results: The incidence of sinus tachycardia and ventricular arrhythmias were similar between groups. Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019).
Conclusions: Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10944733/
Recent studies have focused on the association between thyroid function within normal range and cardiovascular diseases, especially on free triiodothyronine (FT3) levels. This study aims to evaluate the effects of normal FT3 level on new-onset atrial fibrillation (AF) in patients with surgical coronary revascularization.
Methods
The patients who underwent surgical coronary revascularization were enrolled in the retrospective study. Thyroid function was tested after an overnight fast on the first morning of hospitalization. Serum FT3 level was divided into quartile groups within the normal range. Hazards ratios (HRs) of FT3 level for AF were analyzed by COX proportional hazard model.
Results
This study included 503 patients with a mean [standard deviation (SD)] age of 63 (±9) years, and 396 (78.73%) were male. Post-operative AF (POAF) occurred in 120 (23.86%) patients at a median of two days after surgical coronary revascularization. The cumulating incidence of AF was significantly higher in the FT3 quartile 1 (Q1) group especially in older patients as evidenced by Kaplan-Meier analysis. Additionally, the patients who experienced AF had longer hospital stays, the same result was also found in the FT3 Q1 group. Further study demonstrated that low-normal FT3 was an independent predictor of POAF [HR =1.52, 95% confidence interval (CI): 1.01, 2.28, P=0.045].
Conclusions
Low-normal FT3 is associated with an increased risk of POAF and is an independent predictor of POAF. Patients who experienced AF have longer hospital stays. The findings may help to identify patients with surgical coronary revascularization at a higher risk for the development of AF.
The retrospective study proves nothing. So you’ve got 1 small prospective RCT for POAF. I’ll wait to see a more substantive study in that cohort.
As for “ But is it a big part of the solution? Undoubtedly.”… PUH-lease.
Wake me up when you’re prepared to bring some proof.
There are numerous studies linking high T4, and rT3 to atrial fibrillation. I haven’t met a Western doctor yet who prescribes T3. I only see patients who get T4, so they end up with exactly this problem — high T4 and high rT3 and are set up, by their doctors, for A fib.
Nobody is going to do a study showing that doctors are idiots. But there it is.
“Linking”….uh-huh.
You don’t need to do a study to prove that doctors are idiots.
But you do need to do studies that prove whatever nonsense it is that you’re claiming with regards to T3 supplementation. Otherwise, believing in that makes you the idiot.
This is a fantastic autopsy of a clinical blind spot.
Thank you for the reminder that biological plausibility is often the "siren song" that leads us away from objective evidence.
The Andexanet Alfa story is a $20,000 lesson in why "common sense" can be a dangerous guide.
The logic was simple: if a patient is bleeding on a blood thinner, cancel the drug out.
It worked in a lab, but the human body is more complex than a test tube.
The mistake was focusing on chemistry over patients.
The drug reversed the thinner but tipped the scales too far, causing a 6.5% stroke rate.
Stopping a bleed is a hollow victory if the treatment causes a massive clot instead.
For years, we prioritized test results over actual survival.
Your post is a vital prompt for all of us to stay disciplined and demand proof of benefit before adopting the next "breakthrough."
Could some type of companion diagnostic to better know which way the scales will tip…not a hematologist but is it about dosage of the anti- then the dosage of reversal?
Genuine question: Are surrogate endpoints ever a valid method for assessing safety and efficacy of a drug or medical intervention?
I am not actually qualified to respond so please take with a grain of salt. I think the answer is yes, sometimes. If a new blood pressure drug reduced blood pressure substantially, perhaps that would be enough, for instance. But in general it sure would be nice to have clinically meaningful health outcomes rather than surrogate markers such as blood pressure.
Yes, when they are predictive, which some surrogates are. The Accelerated Approval approach allowing surrogates was originally introduced in 1992 to speed up drug development for HIV and it was a resounding success for that because the surrogates (CD4 count, viral load) were predictive. In oncology, the surrogates are not so good.
For me, the main factor is whether clinical endpoints can be measured in a timely fashion. If not (e.g., statin studies), then a surrogate that is proven to be highly correlated with the clinical outcome (e.g., cholesterol levels) is a reasonable endpoint for the initial approval. If there's no reason a relevant clinical endpoint can't be used, I expect the manufacturer to invest the time and money to conduct a trial adequately powered for real outcomes that matter to patients.
I am so happy to use no drugs nearing age 76. How would I ever know which toxic drug is the safest? The FDA?
Having worked on apixaban from first-in-human to the pediatric extensions, I can honestly tell you that BMS never really wanted to help develop an “antidote”. The FDA wanted a reversal agent as did clinicians. I wrote the Clinical Overview for label change for Portola based on ANEXXA studies and we all felt it was a thin package to support full approval. Even then, we knew 4-factor PCC worked OK with no real thrombotic rebound. The tail wagged the dog and I’m glad this got taken off the market. For the Factor XI inhibitors being developed now, the same thing went on initially, but I think PCC and rVIIa will be the reversal strategy.
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.