Would it be different for anticoagulant plus clopidogrel? Especially for patients with high burden of atherosclerosis. Is there something uniquely bad about aspirin as an antiplatelet?
Just to show that clinical decision making can't always be dependent on controlled studies let me present my case.
I had significant mitral prolapse since childhood which grew slowly worse echocardiographically over the years leading to a mitral valve repair after an episode of AF around 2012. Post-op coumadin was stopped after a month or so but I was started on Xarelto after recurrent atrial flutter/fib requiring cardioversion and eventually ablation. A have a giant L atrium, residual moderate MR and short runs of SV rhythm on holter.
Around age 35, in the 1970's and well before my cardiac problem became an issue, I started getting episodes of ophthalmic migraine, with transient loss of a quarter or half my visual field, as I recall in one eye. (Subsequent imaging in later years showed no gross cerebrovascular disease.) It was pretty scary. I self treated with low dose ASA (that's how we treated TIA's in those days) and the episodes abruptly went away so I kept taking it and resumed it after my valve surgery.
Eventually I questioned the need and advisability of keeping up the aspirin and stopped it. About a week later I got a significant episode of scintillating scotoma which concerned me and I went back on 3 days a week with no further problem and I'd been on that for the last few years.
My EP guy is sympathetic but still says I ought to try cutting back more, so now I'm on 2 days a week for the past year. I've had one tiny episode of questionable recurrent scintillating scotoma.
I bleed a little extra if I cut myself and bruise a little easier but not much. Not much out of the ordinary for age 87.
Aspirin (and clopidegrel and prasugrel and ticagreglor) are anti platelet , warfarin and DACs work on various parts of the clotting cascade. Different mechanisms. I think some in here are assuming they all do the same thing. Aspirin has been shown in decent randomized trials to NOT be effective in AF stroke prevention while warfarin and DACs are, hence the need to stay on those. The different mechanisms were why it was thought AF and CAD people would need both, it is always good to confirm theories work (or in this case do not work) via randomized studies!
Raise your hand if you are surprised that taking two anti-platelet agents led to more bleeding than taking just one. More important is that the "benefits" of aspirin and other OACs is pretty small and often overwhelmed by the bleeding risk.
Hello, anesthesiologist from the same center as the first author here. In our center, anesthesiologists manage the perioperative settings and we see a lot of these bleeding complications.
My 2 cents here : the main issue is bleeding : patients stops their medications, are stressed, get anaemic, are hospitalized, etc. which can lead to more ischemic events.
Thanks to the authors and dozen of people working with them for this study and for this blog post.
I wonder if the duration of ASA / anti platelet treatment post stint intervention in pts on NOAC /Warfarin Should be revisited. I find our cardiologist colleagues very protective of their devices often continuing anti platelet therapy for years even while patients are taking NOAC/ASA.
As a PCP who doesn’t look at the literature, this is the most directly applicable article I’ve read on SM. Thank you! Easy answer to stop ASA every time I see a patient with both CAD and A-fib.
Asprin and DHA may have a paradoxical interaction that increases thrombotic events. Patients with a stent may be taking more fish oil than other people. ChatGPT helped me come up with this best explanation:
"1. Aspirin acetylation of COX-2 in a DHA-rich milieu alters lipid-mediator balance toward pro-inflammatory or vasoconstrictive species instead of pro-resolving ones.
2. DHA enrichment of platelet membranes modifies thromboxane and isoprostane signaling so aspirin’s antiplatelet effect is functionally blunted or reversed.
3. High DHA oxidation under aspirin’s pro-oxidant conditions generates lipid peroxides that promote endothelial dysfunction and plaque instability.
4. Aspirin-triggered lipid mediator production from DHA competes with EPA-derived resolvins, reducing net anti-inflammatory and anti-thrombotic protection.
5. Combined aspirin + DHA shifts eicosanoid flux away from balanced homeostasis, producing transient hyper-reactivity or rebound thrombosis after platelet turnover."
Fish oil appears to cause AF. But note that that would not be a relevant mechanism here in and of itself, as background fish oil use would be equal. It's the interaction that would matter, with or without AF.
Other suggestions:
Could there be unblinding caused by aspirin use which changes behavior in a deadly way? Feeling protected makes one more lax? Or could aspirin be effective at reducing angina symptoms and a person exerts themselves to death or takes their health less seriously? Promotes silent ischemia?
In the last 10 years of my 40 years of working in Cardiac Rehab, we experienced a huge increase in CAD pts who also had AF prior to their CAD event. Most of them had ASA added to their meds at the time of CAD event. Most had been taking an anticoagulant prior to CAD event. I remember many patients complaining of easy or unexplained bruising. Most of the docs we consulted said the patient would need to stay on both meds. That was 3 years ago. Maybe this trial will improve patient outcomes in our community.
Your summation of “Plausible but wrong” is my favorite line. Without proper studies we never get to the ‘wrong’ Thank you for bringing new information and insight to us all. As a patient and non medical person your work with Sensible Medicine has educated me (even if some of it is over my head :) and helped me be a better advocate for my own healthcare.
As a gastroenterologist in clinical practice for over 30 years, I’ve been summoned to the emergency department and ICU countless nights for patients bleeding on dual anti-thrombotic (DAT) therapy, typically ASA in combination with warfarin or another anticoagulant. I’ve been de-escalating those patients and almost every other patient on DAT I encounter to a single anti-thrombotic, citing the known increased risk of hemorrhage from DAT and the conspicuous lack of demonstrated benefit for most patients. The AQUATIC trial has provided strong evidence this is the right thing to do; thank you for covering it here.
I don’t understand how this trial supports that conclusion. The two arms were: OAC + ASA or OAC + placebo. The third option, ASA + placebo, was not tested.
Well of course that was not tested, because drug companies would never want you to show that ASA alone is equal to or better than ASA + their $800/month drug.
(“As of late 2025, the average retail price of Eliquis is approximately $830 for a 30-day supply of 60, 5 mg tablets.” — Brave AI)
It was not tested because aspirin has been compared to an anticoagulant in this setting before and there’s no question it’s inferior. There’s no reason to test it again. It has nothing to do with pharmaceutical companies’ greed which is undoubtedly present in many instances, but not related to these findings.
Because we already know from previous RCTs, meta analyses and systematic reviews that OAC (or cheap warfarin) is superior to ASA alone for high risk A-fib. The question has been if there’s additional CAD (which usually means ASA for risk reduction), should we keep ASA?
Good question. In practice, I think the answer lies in the clinical indication for anti-thrombotic therapy with any given patient. Most of the time, I’ll reach out to the patient’s cardiologist or vascular surgeon for advice, and most of the time, they’re pretty good about de-escalating to a single-agent as we go through the indications and guidelines. And you’re correct: that usually leads to stopping the ASA and continuing with an anticoagulant.
I have ripped into guideline writers increasingly in recent years. But in this case, at least in Canada, the antiplatelet and AF writers were ahead of the curve. We haven’t used combo OAC and ASA for years in those with chronic coronary syndromes and AF.
Can’t exclude that they were right, for the wrong reasons. But their decision to go with the earlier smaller studies proved prescient in this case.
In Canada, the general practice for a number of years has been to use only OAC in those with AF + CCS. We generally have not had such pts on ASA for a long while.
For those post ACS or recent PCI, we have been guided by the Augustus trial protocol, as the local preference is for apixaban. Based on that, such pts get up to a month of ASA during “triple therapy”, but most of us do 1 week. Then after 1 year when P2Y12 (clopidogrel in our case) is stopped, they remain on OAC mono therapy thereafter.
The journals to which I subscribe and which I read,NEJM,Annals,and JCO primarily are crammed with clinical trials designed to suggest a clinical benefit for product X,particularly the latter publication.It is maddening,and fraudulent.Kudos for shedding a tiny bit of light into what seems to be a deepening pool of darkness…
Would it be different for anticoagulant plus clopidogrel? Especially for patients with high burden of atherosclerosis. Is there something uniquely bad about aspirin as an antiplatelet?
Just to show that clinical decision making can't always be dependent on controlled studies let me present my case.
I had significant mitral prolapse since childhood which grew slowly worse echocardiographically over the years leading to a mitral valve repair after an episode of AF around 2012. Post-op coumadin was stopped after a month or so but I was started on Xarelto after recurrent atrial flutter/fib requiring cardioversion and eventually ablation. A have a giant L atrium, residual moderate MR and short runs of SV rhythm on holter.
Around age 35, in the 1970's and well before my cardiac problem became an issue, I started getting episodes of ophthalmic migraine, with transient loss of a quarter or half my visual field, as I recall in one eye. (Subsequent imaging in later years showed no gross cerebrovascular disease.) It was pretty scary. I self treated with low dose ASA (that's how we treated TIA's in those days) and the episodes abruptly went away so I kept taking it and resumed it after my valve surgery.
Eventually I questioned the need and advisability of keeping up the aspirin and stopped it. About a week later I got a significant episode of scintillating scotoma which concerned me and I went back on 3 days a week with no further problem and I'd been on that for the last few years.
My EP guy is sympathetic but still says I ought to try cutting back more, so now I'm on 2 days a week for the past year. I've had one tiny episode of questionable recurrent scintillating scotoma.
I bleed a little extra if I cut myself and bruise a little easier but not much. Not much out of the ordinary for age 87.
What should I do now?
Aspirin (and clopidegrel and prasugrel and ticagreglor) are anti platelet , warfarin and DACs work on various parts of the clotting cascade. Different mechanisms. I think some in here are assuming they all do the same thing. Aspirin has been shown in decent randomized trials to NOT be effective in AF stroke prevention while warfarin and DACs are, hence the need to stay on those. The different mechanisms were why it was thought AF and CAD people would need both, it is always good to confirm theories work (or in this case do not work) via randomized studies!
Ok giving both is bad. But which one is best?
Raise your hand if you are surprised that taking two anti-platelet agents led to more bleeding than taking just one. More important is that the "benefits" of aspirin and other OACs is pretty small and often overwhelmed by the bleeding risk.
Hello, anesthesiologist from the same center as the first author here. In our center, anesthesiologists manage the perioperative settings and we see a lot of these bleeding complications.
My 2 cents here : the main issue is bleeding : patients stops their medications, are stressed, get anaemic, are hospitalized, etc. which can lead to more ischemic events.
Thanks to the authors and dozen of people working with them for this study and for this blog post.
I wonder if the duration of ASA / anti platelet treatment post stint intervention in pts on NOAC /Warfarin Should be revisited. I find our cardiologist colleagues very protective of their devices often continuing anti platelet therapy for years even while patients are taking NOAC/ASA.
As a PCP who doesn’t look at the literature, this is the most directly applicable article I’ve read on SM. Thank you! Easy answer to stop ASA every time I see a patient with both CAD and A-fib.
Dr. John, I have a proposed explanation:
https://pubmed.ncbi.nlm.nih.gov/33964664/
Asprin and DHA may have a paradoxical interaction that increases thrombotic events. Patients with a stent may be taking more fish oil than other people. ChatGPT helped me come up with this best explanation:
"1. Aspirin acetylation of COX-2 in a DHA-rich milieu alters lipid-mediator balance toward pro-inflammatory or vasoconstrictive species instead of pro-resolving ones.
2. DHA enrichment of platelet membranes modifies thromboxane and isoprostane signaling so aspirin’s antiplatelet effect is functionally blunted or reversed.
3. High DHA oxidation under aspirin’s pro-oxidant conditions generates lipid peroxides that promote endothelial dysfunction and plaque instability.
4. Aspirin-triggered lipid mediator production from DHA competes with EPA-derived resolvins, reducing net anti-inflammatory and anti-thrombotic protection.
5. Combined aspirin + DHA shifts eicosanoid flux away from balanced homeostasis, producing transient hyper-reactivity or rebound thrombosis after platelet turnover."
Fish oil appears to cause AF. But note that that would not be a relevant mechanism here in and of itself, as background fish oil use would be equal. It's the interaction that would matter, with or without AF.
Other suggestions:
Could there be unblinding caused by aspirin use which changes behavior in a deadly way? Feeling protected makes one more lax? Or could aspirin be effective at reducing angina symptoms and a person exerts themselves to death or takes their health less seriously? Promotes silent ischemia?
Many patients nowadays are taking large doses of vitamin D. Doesn’t that behavior increase bleeding risk with Anti-coagulation + ASA?
In the last 10 years of my 40 years of working in Cardiac Rehab, we experienced a huge increase in CAD pts who also had AF prior to their CAD event. Most of them had ASA added to their meds at the time of CAD event. Most had been taking an anticoagulant prior to CAD event. I remember many patients complaining of easy or unexplained bruising. Most of the docs we consulted said the patient would need to stay on both meds. That was 3 years ago. Maybe this trial will improve patient outcomes in our community.
Your summation of “Plausible but wrong” is my favorite line. Without proper studies we never get to the ‘wrong’ Thank you for bringing new information and insight to us all. As a patient and non medical person your work with Sensible Medicine has educated me (even if some of it is over my head :) and helped me be a better advocate for my own healthcare.
Thank you for the information. Sharing
As a gastroenterologist in clinical practice for over 30 years, I’ve been summoned to the emergency department and ICU countless nights for patients bleeding on dual anti-thrombotic (DAT) therapy, typically ASA in combination with warfarin or another anticoagulant. I’ve been de-escalating those patients and almost every other patient on DAT I encounter to a single anti-thrombotic, citing the known increased risk of hemorrhage from DAT and the conspicuous lack of demonstrated benefit for most patients. The AQUATIC trial has provided strong evidence this is the right thing to do; thank you for covering it here.
Curious if you had preference for which agent to stop before AQUATIC? Super helpful to know AQUATIC clearly suggests we stop ASA.
“AQUATIC clearly suggests we stop ASA.”
I don’t understand how this trial supports that conclusion. The two arms were: OAC + ASA or OAC + placebo. The third option, ASA + placebo, was not tested.
Well of course that was not tested, because drug companies would never want you to show that ASA alone is equal to or better than ASA + their $800/month drug.
(“As of late 2025, the average retail price of Eliquis is approximately $830 for a 30-day supply of 60, 5 mg tablets.” — Brave AI)
It was not tested because aspirin has been compared to an anticoagulant in this setting before and there’s no question it’s inferior. There’s no reason to test it again. It has nothing to do with pharmaceutical companies’ greed which is undoubtedly present in many instances, but not related to these findings.
Because we already know from previous RCTs, meta analyses and systematic reviews that OAC (or cheap warfarin) is superior to ASA alone for high risk A-fib. The question has been if there’s additional CAD (which usually means ASA for risk reduction), should we keep ASA?
Good question. In practice, I think the answer lies in the clinical indication for anti-thrombotic therapy with any given patient. Most of the time, I’ll reach out to the patient’s cardiologist or vascular surgeon for advice, and most of the time, they’re pretty good about de-escalating to a single-agent as we go through the indications and guidelines. And you’re correct: that usually leads to stopping the ASA and continuing with an anticoagulant.
I have ripped into guideline writers increasingly in recent years. But in this case, at least in Canada, the antiplatelet and AF writers were ahead of the curve. We haven’t used combo OAC and ASA for years in those with chronic coronary syndromes and AF.
Can’t exclude that they were right, for the wrong reasons. But their decision to go with the earlier smaller studies proved prescient in this case.
Curious if you knew which to stop? Super helpful to know AQUATIC suggests stopping ASA.
In Canada, the general practice for a number of years has been to use only OAC in those with AF + CCS. We generally have not had such pts on ASA for a long while.
For those post ACS or recent PCI, we have been guided by the Augustus trial protocol, as the local preference is for apixaban. Based on that, such pts get up to a month of ASA during “triple therapy”, but most of us do 1 week. Then after 1 year when P2Y12 (clopidogrel in our case) is stopped, they remain on OAC mono therapy thereafter.
The journals to which I subscribe and which I read,NEJM,Annals,and JCO primarily are crammed with clinical trials designed to suggest a clinical benefit for product X,particularly the latter publication.It is maddening,and fraudulent.Kudos for shedding a tiny bit of light into what seems to be a deepening pool of darkness…