Aspirin meta-analysis study (focus on bleeds and cancer)

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pellicle

pellicle

Professional Dingbat, Guru and Merkintologist
Joined
Nov 4, 2012
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Location
Queensland, OzTrayLeeYa
Probably the best lecture I've ever sat through. So, well worth watching this lecture:


I in particular loved his opening address, giving credit to so many and the caution against selecting studies that reenforce your starting biases.

Touches on my usual key points too
  • compliance failures
  • lack of interest in studying a drug which is not going to make Pharma a lot of money
 
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also from the transcript starting at 9:31 >>

Now before I present any clinical evidence let me just make three principles about research.​
​
First of all my boss in the my early years in Cardiff Archie Cochran, of this University, he very effectively publicized the principle that; in evaluating evidence it's essential at all available evidence is considered and never just a selection.​
​
It's awfully easy to have a hypothesis and spend a Friday afternoon going through the literature and finding one or two Publications that show the same kind of thing as we're looking for in that particular hypothesis. That is so misleading it should never be done. So he went to enormous efforts as you will see in what follows that we would collect all the available evidence.​
​
Then the follower of other modern medicines William Moser he said I think it sums up "medicine is a science of uncertainty and an art of probability". In the end science never proves anything, always [it is] another explanation and conclusions about a particular hypothesis [and] can only be established at best to be Beyond Reasonable Doubt.​
​
Don't look to me for any certainty in what I say but I think we've established a number of important steps which go beyond Reasonable Doubt.​
[bold mine]

Sage words.
 
pellicle said:
Probably the best lecture I've ever sat through. So, well worth watching this lecture:


I in particular loved his opening address, giving credit to so many and the caution against selecting studies that reenforce your starting biases.

Touches on my usual key points too
  • compliance failures
  • lack of interest in studying a drug which is not going to make Pharma a lot of money
Click to expand...
 
Two months ago I stopped my 81 mg/day aspirin. The stoppage was recommended by an ER doctor after my stomach bleed, more specifically, the duodenum. I knew it was happening by noticing black stools but I had more important things to do, so I thought, and by the time I went to the ER my hemoglobin was 6.9 mg/dl (normal for men is 13.1-17.5 mg/dl). My red blood count was similarly about half normal. It was difficult just to walk. I've been monitoring HBG and RBC because of hemolysis which is much improved since the fix of my valve leak in Nov '23.

After listening to the lecture posted by pellicle, I'm considering restarting aspirin maybe at half the dose or taking the 81 mg every other day. The aspirin was originally recommended by my cardiologist.

On a related topic, I recently asked my cardiologist if I could stop statins because of some papers I read that statin drugs are causing more problems than they are solving: For an example click here. And over a decade ago I read the Jupiter study which concluded that statin therapy did indeed reduce cardiovascular event rates from atherogenesis but the benefits were more related to the statin's anti-inflammatory properties than its cholesterol lowering properties. Well aspirin is a great anti-inflammatory drug and it's a lot cheaper than statins. The cited example study from Japan was published in 2015 so I thought that in all those years, new evidence in support of statins had superseded it. However, I'm still seeing articles saying statins can exacerbate CHF, joint pain, arteriolosclerosis, energy deficit, DNA damage, vitamin K2 deficiency and more.

When I asked my cardiologist about stopping statins based on these studies, here is his answer:
"The data on statins is extraordinarily positive. The recent studies talking about coronary calcium and statins are completely misconstruing what is happening. With statins, calcification increases because there is healing of plaque. Statins are anti-inflammatory as well as antiatherosclerotic. They are the backbone of preventing problems in your vein bypasses, and they have been utilized since 1990 . Not a single well done study suggests that there is a deleterious effect on cerebral function, long-term liver function, cardiac muscle function, or coronary artery disease. There are some people with genetic alterations that have muscle problems but that manifests itself in a fulminant way. Statins can exacerbate glucose intolerance and in patients who are destined to have diabetes, accelerate the onset of the diabetes by about 6 months. Statins can be associated with osteoporosis, in sedentary people with poor diets. I would not be in a rush to stop it."
 
Dana said:
Two months ago I stopped my 81 mg/day aspirin. The stoppage was recommended by an ER doctor after my stomach bleed, more specifically, the duodenum. I knew it was happening by noticing black stools but I had more important things to do, so I thought, and by the time I went to the ER my hemoglobin was 6.9 mg/dl (normal for men is 13.1-17.5 mg/dl). My red blood count was similarly about half normal. It was difficult just to walk. I've been monitoring HBG and RBC because of hemolysis which is much improved since the fix of my valve leak in Nov '23.

After listening to the lecture posted by pellicle, I'm considering restarting aspirin maybe at half the dose or taking the 81 mg every other day. The aspirin was originally recommended by my cardiologist.

On a related topic, I recently asked my cardiologist if I could stop statins because of some papers I read that statin drugs are causing more problems than they are solving: For an example click here. And over a decade ago I read the Jupiter study which concluded that statin therapy did indeed reduce cardiovascular event rates from atherogenesis but the benefits were more related to the statin's anti-inflammatory properties than its cholesterol lowering properties. Well aspirin is a great anti-inflammatory drug and it's a lot cheaper than statins. The cited example study from Japan was published in 2015 so I thought that in all those years, new evidence in support of statins had superseded it. However, I'm still seeing articles saying statins can exacerbate CHF, joint pain, arteriolosclerosis, energy deficit, DNA damage, vitamin K2 deficiency and more.

When I asked my cardiologist about stopping statins based on these studies, here is his answer:
"The data on statins is extraordinarily positive. The recent studies talking about coronary calcium and statins are completely misconstruing what is happening. With statins, calcification increases because there is healing of plaque. Statins are anti-inflammatory as well as antiatherosclerotic. They are the backbone of preventing problems in your vein bypasses, and they have been utilized since 1990 . Not a single well done study suggests that there is a deleterious effect on cerebral function, long-term liver function, cardiac muscle function, or coronary artery disease. There are some people with genetic alterations that have muscle problems but that manifests itself in a fulminant way. Statins can exacerbate glucose intolerance and in patients who are destined to have diabetes, accelerate the onset of the diabetes by about 6 months. Statins can be associated with osteoporosis, in sedentary people with poor diets. I would not be in a rush to stop it."
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Your cardiologist is spot on about statins. There is a lot of misinformation about statins online- one of the favorite boogeymen of the alternative medicine crowd.

Scientist Dr. Gil Carvalho does a good job of covering the published medical literature here:

 
Truly great video on Aspirin. Very valuable.

The discussion on statins is also super valuable. I rejected being on them for years. My LDL and my total have always been off the charts. Even with a perfect diet I am at the max limit (which is still too much). Finally accepted statins about 6 months ago. Started off slow. In fact, just gave some blood to test for elevated liver enzymes because during a recent ER visit (no worries, just a kidney stone), I noticed elevated liver enzymes (not drastic at all, but elevated outside of the range and obviously higher than before). Have a virtual visit with my cardio this Friday to review the results and make adjustments if necessary. FWIW, I’m on 200mg of Ubiquinol (CoQ10) too.
 
Hi

Dana said:
I stopped my 81 mg/day aspirin. The stoppage was recommended by an ER doctor after my stomach bleed, more specifically, the duodenum. I knew it was happening by noticing black stools but
Click to expand...
did you ever get to the cause of the bleeding?

I'm considering restarting aspirin maybe at half the dose or taking the 81 mg every other day. The aspirin was originally recommended by my cardiologist.
Click to expand...
without a cause for the bleeding it may still be happening but at a much reduced (barely observable level). If you've got that resolved then all good ...

Statins can exacerbate glucose intolerance and in patients who are destined to have diabetes, accelerate the onset of the diabetes by about 6 months
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this is interesting wording ... I think there is an amount of "willfull ignorance" in the medical fields about the negatives on statins because they are "superficial" and "focused on the benefits". It wouldn't be the first time (although this specific one was so bad its the exemplar)
1705953360490.png


What's of course hard is teasing out what may be "distorted" and what may be actual", personally I think that what Chuck has said above is on the money.

My own view is that the effects of Aspirin are born out statistically over a duration and are not something that you feel. I'm not aware of any studies that have looked at optimising dose, however what we know about Aspirin is this:
  • Aspirin is rapidly absorbed in the upper gastrointestinal (GI) tract and results in a measurable inhibition of platelet function within 60 minutes
  • The plasma half-life of aspirin is only 20 minutes; however, because platelets cannot generate new COX, the effects of aspirin last for the duration of the life of the platelet (≈10 days). After a single dose of aspirin, platelet COX activity recovers by ≈10% per day as a function of platelet turnover
See this post for some more details

so my own strategy is to have my aspirin dose every other day (and to avoid doubling up it means I load 4 in my 7day box one week {Su, Tue, Th, Sa} and 3 the next {Mo, We, Fr})

sofar this works for me and I have observed that I have less trouble when I bash myself while working.

HTH

Best Wishes
 
pellicle said:
so my own strategy is to have my aspirin dose every other day (and to avoid doubling up it means I load 4 in my 7day box one week {Su, Tue, Th, Sa} and 3 the next {Mo, We, Fr})
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Sounds like a plan. I think I will try that too.
No, never actually figured out what caused the bleed. All my own theories (OD of iron which I take to help with the hemolytic anemia, zinc) were rejected by various doctors that I asked. So the only thing left was aspirin which is known to increase risk of bleeds. But it's not clear by exactly how much it increases risk, (not much according to the video). I'm assuming it's dose-related and cutting the dose in half should help and if the COX recovery is 10% per day then the effective half-live is 5 days, although it's not really a half life because half-life decay is exponential whereas 10% per day is linear. But the point is that in light of the slow recovery of COX activity, taking aspirin every other day should not diminish its benefit much.
 
Hi

Dana said:
Sounds like a plan. I think I will try that too.
No, never actually figured out what caused the bleed.
Click to expand...

well, in that case I'd suggest keeping an eye on your stools (which you probably do now anyway.

. I'm assuming it's dose-related and cutting the dose in half should help
Click to expand...
no, its not actually dose related, its something different. Dose related would be how much aspirin destroyes how much platelet ... (which is where the COX is generated).
This is an alternating scheme which is based on giving a whole day for more platelets to be generated (which are stamped out at a rate that's perhaps unknown, but do have a life of about 10 days (or that's the best figure I can get).

Thus the body mechanisms have a day to stamp out more platelets creating a rise in platelets that are not damaged.

and if the COX recovery is 10% per day then the effective half-live is 5 days,
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I don't think that maths follows, but its also worth mentioning there is no COX recovery, once damaged the platelet is damaged, it needs to be replaced. I am unsure if there is any 'damage detection and correction mechanism' in place.

although it's not really a half life because half-life decay is exponential whereas 10% per day is linear.
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correct ... its not really a half life
 
I didn't read the papers referred to in the presentation, so I didn't see what dosages were used in the various studies.

Without knowing the dosages - 325 mg? 650 mg?? 81 mg? it's a bit difficult to fully understand the results.

FWIW - enteric coated aspirin (I take enteric coated 81 mg aspirin daily - I just restarted it), doesn't dissolve in the stomach. An enteric coated aspirin may be able to avoid/reduce your gastric issues with aspirin.

And, FWIW - the half life of platelet regeneration doesn't depend on the dose - it's still ten days. (Otherwise, as suggested, taking half as much aspirin as you used to would reduce the half life to 5 days - by that logic, taking 1/4 dose would reduce it to 2.5 days - and this reasoning just doesn't work)
 
Dana said:
Statins can exacerbate glucose intolerance and in patients who are destined to have diabetes, accelerate the onset of the diabetes by about 6 months.
Click to expand...
This is generally accurate. However, this varies significantly from statin to statin. Most statins do increase insulin resistance and increase the risk of developing prediabetes and diabetes. However, there are a few statins which do not. I'm on pitavastatin, because studies have found that it does not increase insulin resistance. See linked studies below. There is another study, not linked below, which found that pitavastatin actually increased insulin sensitivity slightly.

Pitavastatin is still in patent, so it's more expensive. If this is an issue I would discuss choosing Crestor(rosuvastatin) over Lipitor(atorvastatin) with your doctor. Lipitor is about the worst offender when it comes to increasing insulin resistance- Crestor much less so. Both are out of patent, so they are dirt cheap. Also, the effects on insulin resistance are dose dependant. So, ideally, the lowest dose of statin to get you to your cardiologist's LDL goal would be a good idea. As your cardiologist noted, there are many benefits of statins besides lowering LDL, including stabilizing vulnerable plaques and decreasing arterial inflammation. Crestor has been shown to be very effective at both of these pleiotropic benefits, even at low dose.

Two linked studies below on pitavastatin:

"4) Conclusions: The present study did not show a significant change in serum adiponectin or HMW adiponectin from baseline in serum adiponectin following pitavastatin therapy. Although statin has been considered as a risk for dysglycemia, pitavastatin did not affect insulin sensitivity."

https://www.mdpi.com/2077-0383/11/2...e present,did not affect insulin sensitivity.
"Conclusion
Compared with placebo, pitavastatin did not affect hepatic or whole-body insulin sensitivity, and it did not reduce liver fat."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194811/
 
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pellicle said:
no, its not actually dose related, its something different. Dose related would be how much aspirin destroyes how much platelet ... (which is where the COX is generated).
This is an alternating scheme which is based on giving a whole day for more platelets to be generated (which are stamped out at a rate that's perhaps unknown, but do have a life of about 10 days (or that's the best figure I can get).

Thus the body mechanisms have a day to stamp out more platelets creating a rise in platelets that are not damaged.
Click to expand...
I was hoping that the bleed risk would diminish with dose decrease. If bleed risk correlates with platelet inhibition, a smaller aspirin dose should affect fewer platelets and should result in less platelet inhibition therefore less bleed risk, but probably less cardiovascular benefit. Keeping the dose constant and instead decreasing dosing frequency should not reduce platelet inhibition much because of the persistence and irreversibility of COX-1 inhibition for the life of the platelet.

But which of these strategies (decreased dose or frequency) would meet the goal of reducing bleed risk but maintaining the cardiovascular benefit?

Confused, I again asked my cardiologist, and also asked if neither approached worked then is there an alternative drug to aspirin that would achieve the goal? His answer is below. Note that he says I have a perfect brain (I don't need a "new brain", - unlike the Monty Python episode). Unfortunately, all he means is that my brain has not had an embolic event.

"Thank you for your question and for your thoughtful analysis. We use the baby aspirin combined with the warfarin in patients with mechanical valves to prevent clots from forming on the valves. If the INR was always above 3.5 we would not even have to think about this, but we can get away with an INR that drops to 2.8 or even 2.5 occasionally, when the person is on some dose of aspirin. Additionally, the aspirin is beneficial for the bypass grafts, though the warfarin probably has a similar effect. Your brain has stayed perfect and we have never had an embolic event, thus I like the idea of a bit of platelet inhibition. Aspirin 81 mg 3 times per week is probably every bit as effective his aspirin daily in terms of preventing clotting, and the bleeding risks is less-because we are occupying fewer of the platelet receptors-not inhibiting as completely cyclooxygenase. So why don't we try ASA 81 mg 3 times each week. Additionally, we would usually use some agent such as Pepcid-famotidine or omeprazole or pantoprazole to decrease acid in the gut. Famotidine-Pepcid can be utilized long-term even at a low dose, 20 mg daily."

So bottom line: aspirin 3x per week. Similar to what @pellicle said he is doing.

BTW, my body does not like an INR above 3.5. The GI bleed occurred when my INR was inadvertently at 4.0.
 
Dana said:
I was hoping that the bleed risk would diminish with dose decrease. If bleed risk correlates with platelet inhibition, a smaller aspirin dose should affect fewer platelets and should result in less platelet inhibition therefore less bleed risk, but probably less cardiovascular benefit. Keeping the dose constant and instead decreasing dosing frequency should not reduce platelet inhibition much because of the persistence and irreversibility of COX-1 inhibition for the life of the platelet.

But which of these strategies (decreased dose or frequency) would meet the goal of reducing bleed risk but maintaining the cardiovascular benefit?

Confused, I again asked my cardiologist, and also asked if neither approached worked then is there an alternative drug to aspirin that would achieve the goal? His answer is below. Note that he says I have a perfect brain (I don't need a "new brain", - unlike the Monty Python episode). Unfortunately, all he means is that my brain has not had an embolic event.

"Thank you for your question and for your thoughtful analysis. We use the baby aspirin combined with the warfarin in patients with mechanical valves to prevent clots from forming on the valves. If the INR was always above 3.5 we would not even have to think about this, but we can get away with an INR that drops to 2.8 or even 2.5 occasionally, when the person is on some dose of aspirin. Additionally, the aspirin is beneficial for the bypass grafts, though the warfarin probably has a similar effect. Your brain has stayed perfect and we have never had an embolic event, thus I like the idea of a bit of platelet inhibition. Aspirin 81 mg 3 times per week is probably every bit as effective his aspirin daily in terms of preventing clotting, and the bleeding risks is less-because we are occupying fewer of the platelet receptors-not inhibiting as completely cyclooxygenase. So why don't we try ASA 81 mg 3 times each week. Additionally, we would usually use some agent such as Pepcid-famotidine or omeprazole or pantoprazole to decrease acid in the gut. Famotidine-Pepcid can be utilized long-term even at a low dose, 20 mg daily."

So bottom line: aspirin 3x per week. Similar to what @pellicle said he is doing.

BTW, my body does not like an INR above 3.5. The GI bleed occurred when my INR was inadvertently at 4.0.
Click to expand...
Thanks for sharing this Dana.

I really like the well thought out response from your cardiologist. You are fortunate to have a cardiologist who responds to your questions so thoroughly and has a discussion with you about the best way forward.
 
Hi
Dana said:
(I don't need a "new brain", - unlike the Monty Python episode).
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unusually I'm going to ask "which episode is that because I don't recall that" ... I'm a bit weak on Flying Circus TV eps, and mostly focused on LP and the Big Screen releases.

On the subject of platelets, this is from an ATS (valve maker) promotional material for a new coating on their pyrolytic leaflets. I post it because it shows how platelets do bind at some level to the valve surface

1706218487226.png

1706218560947.png


its worth observing that this does not include the sort of flows and flow effects that the valve would get in the living (in-vivo) situation. However this is interesting and also coincidentally makes me wonder about the causes for post-perfusion syndrome...
1706218704891.png


1706218788624.png

1706218836653.png


So it would seem to mitigate against platelet aggregation on the surface (for who long is anyone's guess).

However what is ignored here is the effect of platelet being triggered by jet pressures.

from a paper by Yoganathan 2004:
FLUID MECHANICS OF HEART VALVES
Ajit P. Yoganathan, Zhaoming He, and S. Casey Jones


1706219105061.png


lastly I just love that Casey Jones is a co-author
1706219194999.png
 
pellicle said:
unusually I'm going to ask "which episode is that because I don't recall that" ... I'm a bit weak on Flying Circus TV eps
Click to expand...
Yes, it was a TV episode. New Brain from Currys.
https://montypython.fandom.com/wiki/New_Brain_from_Currys?file=Grandstand6.PNGI found this on YouTube:
pellicle said:
a new coating on their pyrolytic leaflets
Click to expand...

The rest of your post is interesting. I have asked about treating valve leaflets with some non-stick surface. No good answers though. My brother-in-law used to work for a company developing a substance invented by students at Massachusetts Institute of Technology (MIT) that is extremely slippery. He was their business-development officer looking for applications for their product. Of course, I immediately suggested heart valves to prevent hemolysis. He said they were looking into that but so far had no solutions for that environment that would last. Unfortunately the only application they seem to be focusing on is lining ketchup bottles and toothpaste tubes. I told him that neither of those applications is likely to survive a cost-benefit analysis. So you save a few pennies worth of ketchup or toothpaste at what cost for the container lining? Seems dumb to me but their marketing literature brags that it saves waste. As the author of this article states, it solves one of the greatest non-issues of our generation." It would be great if they can figure out how to coat the leaflets of heart valves, though, and have it stand up to a billion heartbeats.
 
No thanks; ever since Nov-2015 when i got the OnX i followed the OnX recommendations about taking 0.81mg a day, did so during 8 years+, had several bleeding events, and based on recommendations from 2 doctors in my family, i stopped the asa, no more bleeding events during past 2 months, So absolutely no doubts that "FOR ME " taking asa = bleeding events, ; as per the Cancer talks all over the world, is NOT the search for the cure for cancer what will change the paradigm, but talking more about "what causes" it, but it is very , very hard to hear about it, although it is still possible to find information about it, for now, everything is changing and sometimes for the better, yes.
 
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