I have wondered the reason of the North American difference. I have heard the floated answers that it was the asa dose difference or chance. The cro explanation, if I am understanding correctly, seems obvious and if it is accurate should not that have been known earlier?
It's easy to create conspiracy theories about mega-trials and spread misinformation based on some sensationalist articles rather than looking carefully at all the evidence. For those of us who actually perform PCI and prescribe ticagrelor, it is an excellent drug because it provides a very consistent level of platelet inhibition and so provides excellent protection against stent thrombosis rather than the lottery of using clopidogrel, which is associated with wide interindividual variation in response - sometimes similar platelet inhibition to ticagrelor (i.e. similar bleeding risk) and sometimes undetectable response (i.e. greater thrombotic risk). We've treated over 10 thousand patients with ticagrelor in our centre so have extensive experience, showing reduction in stent thrombosis. However, it's important to recognise that this is not the only improvement since PLATO was published in 2009. In particular, stents and implantation techniques have markedly improved, so it's harder to demonstrate the benefit of a more potent antiplatelet drug in observational studies. These improvements have now facilitated early de-escalation of antiplatelet therapy after PCI, with aspirin cessation and use of ticagrelor monotherapy providing a very predictable means of de-escalation:
Cost effectiveness may be a concern but this concern will recede when generic versions become available and the important thing is to discuss what is the optimal treatment for our patients in future care.
As a general cardiologist who has prescribed ticag countless times in the last 10 years, this is (insert superlative of choice here) concerning.
And this is concerning at a level far beyond “have I been using the wrong drug” or “have I been using a non cost-effective drug”. This implies, or at least invokes, the possibility of outright fraud in the Plato organization that strikes at the very heart of clinical research and EBM. If we don’t have faith in how the sausage was made….
I’ve never been as charitable as Dr. Mandrola tends to be, vis-a-vis whether some activities are “nefarious”. However, in the past I’ve restricted that view to trial design, or wording of manuscripts, or overt spin during press sessions, or guidelines that do not reflect the foundational studies. Those are easy to spot, and easy to ignore (including guidelines, which in Canada do not reign supreme as they do in the US). So when people are behaving as paid shills, that doesn’t really impact my practice. They simply get ignored.
These Plato revelations are next level stuff, if it is anywhere near to the truth. And this is information that the average clinician trying to appraise clinical research would never be privy to. If one can’t trust the data upon which the study results are based, or represent, due to malfeasance at the level of study conduct, that brings a level of disrepute to the research process that to my knowledge was heretofore unheard of. And I feel this represents a departure from all that came before it.
As long as one accepts a less than 2% real risk reduction as "clinically meaningful and statistically robust" the debates and endless studies will continue and the pharmaceutical tail will continue to wag the medical dog.
Great points here, Dr. M. And there definitely should be a confirmatory trial. Our tax dollars are at stake here. Rather than keep cutting physician pay, why not start by making sure the drugs we are paying for are actually better.
All this complex and convoluted analysis when the problem is simple. You continue to use relative stats and HRs. The real difference is not much over 2%. And these are always population based stats, so for any individual the difference approaches zero. And I often wonder how the initial dose of any medicine is chosen for a trial? Finally, not that I agree, I thought these antiplatelet drugs had been superseded by Class Xa DOCA drugs.
We were also able to show prasgrel's superiority over ticagrelor in routine care when emulating the ISAR-REACT5 trial in observational data inn this JAMA Network Open study from Dec 2024
You are right. The whole “aspirin dose” hypothesis is silly. They pulled that excuse literally right out of their arse. PLATO used mainly 300mg load plavix, whereas most docs use 600mg. The drug eluting stents during that trial were older versions (ie higher thrombosis rates; not applicable to today). I recall being in several conference discussions during that time when heated debates would arise about PLATO limitations/critiques and anytime somebody questioned the results, the answer was to essentially squash any further discussion. I recall getting the sense that nobody really wanted to seriously debate the merits of this trial and they are looking to just get another patented drug approved. Soon after, lots of emergency rooms, chest pain units, ICUs, in the adopted “Brilinta” as the drug of choice for acute coronary syndrome. The side effect of dyspnea was obviously understated in the study. The actual incidence of dyspnea as a result of this drug is much higher and I have had to discontinue it in multiple patients. Patients are always complaining about the out-of-pocket cost. The whole clopidogrel non-responder issue, while real, was highly exaggerated.
So yes, absolutely it’s time to revisit this medication. Will it happen? Doubt it.
I have wondered the reason of the North American difference. I have heard the floated answers that it was the asa dose difference or chance. The cro explanation, if I am understanding correctly, seems obvious and if it is accurate should not that have been known earlier?
It's easy to create conspiracy theories about mega-trials and spread misinformation based on some sensationalist articles rather than looking carefully at all the evidence. For those of us who actually perform PCI and prescribe ticagrelor, it is an excellent drug because it provides a very consistent level of platelet inhibition and so provides excellent protection against stent thrombosis rather than the lottery of using clopidogrel, which is associated with wide interindividual variation in response - sometimes similar platelet inhibition to ticagrelor (i.e. similar bleeding risk) and sometimes undetectable response (i.e. greater thrombotic risk). We've treated over 10 thousand patients with ticagrelor in our centre so have extensive experience, showing reduction in stent thrombosis. However, it's important to recognise that this is not the only improvement since PLATO was published in 2009. In particular, stents and implantation techniques have markedly improved, so it's harder to demonstrate the benefit of a more potent antiplatelet drug in observational studies. These improvements have now facilitated early de-escalation of antiplatelet therapy after PCI, with aspirin cessation and use of ticagrelor monotherapy providing a very predictable means of de-escalation:
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.067767
Cost effectiveness may be a concern but this concern will recede when generic versions become available and the important thing is to discuss what is the optimal treatment for our patients in future care.
Have the authors and/or sponsor commented on the 45 versus 0 events added by later adjudication?
Of all the various concerns, this seems very unlikely to be due to chance and was apparently raised 12 years ago.
Has there been a response on this particular issue? For instance, is there agreement that the 45 versus 0 number is, in fact, correct?
As a general cardiologist who has prescribed ticag countless times in the last 10 years, this is (insert superlative of choice here) concerning.
And this is concerning at a level far beyond “have I been using the wrong drug” or “have I been using a non cost-effective drug”. This implies, or at least invokes, the possibility of outright fraud in the Plato organization that strikes at the very heart of clinical research and EBM. If we don’t have faith in how the sausage was made….
How at this point in time do you have faith in any sausage made?
I’ve never been as charitable as Dr. Mandrola tends to be, vis-a-vis whether some activities are “nefarious”. However, in the past I’ve restricted that view to trial design, or wording of manuscripts, or overt spin during press sessions, or guidelines that do not reflect the foundational studies. Those are easy to spot, and easy to ignore (including guidelines, which in Canada do not reign supreme as they do in the US). So when people are behaving as paid shills, that doesn’t really impact my practice. They simply get ignored.
These Plato revelations are next level stuff, if it is anywhere near to the truth. And this is information that the average clinician trying to appraise clinical research would never be privy to. If one can’t trust the data upon which the study results are based, or represent, due to malfeasance at the level of study conduct, that brings a level of disrepute to the research process that to my knowledge was heretofore unheard of. And I feel this represents a departure from all that came before it.
I agree. It is a massive departure.
High potency cayenne herb tincture is the best stent I have ever used. Maybe even Plato used it.
As long as one accepts a less than 2% real risk reduction as "clinically meaningful and statistically robust" the debates and endless studies will continue and the pharmaceutical tail will continue to wag the medical dog.
One of the PIs on PLATO is a fellow contributor to Medscape Cardiology. Any chance of getting a response from him?
Great points here, Dr. M. And there definitely should be a confirmatory trial. Our tax dollars are at stake here. Rather than keep cutting physician pay, why not start by making sure the drugs we are paying for are actually better.
All this complex and convoluted analysis when the problem is simple. You continue to use relative stats and HRs. The real difference is not much over 2%. And these are always population based stats, so for any individual the difference approaches zero. And I often wonder how the initial dose of any medicine is chosen for a trial? Finally, not that I agree, I thought these antiplatelet drugs had been superseded by Class Xa DOCA drugs.
We were also able to show prasgrel's superiority over ticagrelor in routine care when emulating the ISAR-REACT5 trial in observational data inn this JAMA Network Open study from Dec 2024
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2827186
Hello. I’m not a physician or medical researcher but have a question. Why don’t you prescribe anti-platelet drugs? What do you use instead?
Love Sensible Medicine. Thanks for the content.
I don’t prescribe anti platelet drugs b/c I am a US cardiac electrophysiologist and we don’t do stents.
If nothing else, this article is one more strong piece of evidence that trials need to be confirmed. Stuart Buck please call your office ?
You are right. The whole “aspirin dose” hypothesis is silly. They pulled that excuse literally right out of their arse. PLATO used mainly 300mg load plavix, whereas most docs use 600mg. The drug eluting stents during that trial were older versions (ie higher thrombosis rates; not applicable to today). I recall being in several conference discussions during that time when heated debates would arise about PLATO limitations/critiques and anytime somebody questioned the results, the answer was to essentially squash any further discussion. I recall getting the sense that nobody really wanted to seriously debate the merits of this trial and they are looking to just get another patented drug approved. Soon after, lots of emergency rooms, chest pain units, ICUs, in the adopted “Brilinta” as the drug of choice for acute coronary syndrome. The side effect of dyspnea was obviously understated in the study. The actual incidence of dyspnea as a result of this drug is much higher and I have had to discontinue it in multiple patients. Patients are always complaining about the out-of-pocket cost. The whole clopidogrel non-responder issue, while real, was highly exaggerated.
So yes, absolutely it’s time to revisit this medication. Will it happen? Doubt it.
PLATO was a scam.
The standard dose of Clopidogrel loading in ACS is 600 mg.
In PLATO, Ticagrelor was tested against only 300 mg of Clopidogrel.
substandard and under-dosing of the control arm explains the apparent superiority of Ticagrelor.