It would be interesting to see whether there are differences in primary prevention with aspirin for people who are genetically predisposed to increased blood clotting/thrombosis based on a polygenic risk score...I consult for a company offering consumer genetic testing and I see plenty of people having a higher than average risk for increased blood clotting/thrombosis, with or without other genetic predispositions, but very often accompanied by an increased risk of CVD. (I am not referring here to people with Factor V Leiden mutation, as it is more rare). Any ideas or resources?
Aspirin was stopped abruptly for all the studies I remember where people already taking aspirin were randomized to the placebo group. I know that some people have referred to a rebound effect to abrupt discontinuation but I have never seen any evidence for that. It seems unlikely that would occur given the nature of the effects of aspirin on platelets. Aspirin has a half-life of only about 20 minutes in the circulating blood. It is very quickly metabolized to salicylate which has none of the platelet inhibiting effect. Aspirin will inhibit aggregation of a portion of the platelets in the blood during the period of aspirin activity and this is irreversible during the lifetime of the platelets (about 8-9 days). But the bone marrow is creating billions of new platelets every day and these will not be affected by the prior aspirin dose. Hence the need for daily dosing in order to maintain the desired effects.
On the one hand, looking at a retrospective subgroup with a trial that was negative on the primary endpoint seems like a no-no on first principles.
OTOH, “primary prevention patients already on ASA who have not bled” does maybe select for a plausible subgroup that stands to reap the future benefits of ASA in primary prevention while having an already- demonstrably lower bleeding risk.
As opposed to “starting” ASA for primary prevention, where the answer is clearly no, perhaps de prescribing should be guided by pt preference. Not one size fits all, it would seem. Hopefully better data will be forthcoming (altho not sure who would pay for such a study).
Excellent point. The retrospective subgroup analysis is a favorite trick of the epidemiologists in order to claim some significance for their research. They will point out that females between the ages of 30 and 40 who are non-smokers of Norwegian descent and eat brussel sprouts daily have a lower/higher incidence of disease X than others. I think one of the early examples of this was the Framingham Study---one of the most over-rated ever. They were determined to find a correlation between cholesterol levels and heart disease but, unfortunately, it didn't pan out. They then broke down the data further and discovered that there was a correlation (albeit a weak one) for males under the age of 50. Unfortunately zero correlation for males over 50 and females of any age.
Aspirin withdrawal itself causes a rebound and that could also bias the results.
FYI one observational study finds aspirin with fish oil is associated with increased death. There's a non-obvious interaction.
In those with heart disease from what I can tell the limited number of studies that use very low doses like 20 mg of aspirin look like it may work almost as well. 81 mg seems to be incidental instead of optimal.
Modern medicine needs to get wise to nattokinase. Recent retrospective study found like a 30% reduction in carotid plaque among other good things. Even more if combined with aspirin. No reported side effects. I have a couple concerns but it probably beats the crap out of everything else.
I was hospitalized with a perforated ulcer which was exacerbated by taking aspirin as it caused severe damage to my stomach lining. If the benefit is minimal, I would say skip it. Thanks for the post. It seems doctors rarely admit when they are wrong. sabrinalabow.substack.com
I disagree with the statement that this is a tough call. Clearly there is no benefit in taking daily aspirin in patients without a history of cardiovascular disease. The absolute risk reduction in the major end points for ASCEND was 1.1%. For ARRIVE 0.19%. ASPREE showed a difference of 0.6 events per 1000 person-years. The figures given in the article were obviously Relative Risk Reductions and , therefore, extremely misleading when dealing with these low rates of event occurrence. The British Medical Journal reported a "Collaborative Overview of Randomized Trials of Anti-Platelet Therapy" in 1994 that combined the results of 174 trials using low dose aspirin or other platelet inhibiting drugs. These involved various different categories of patients---with or without CV disease. The results were remarkably similar to those reported in the article---1.1% reduction in total mortality and nonfatal myocardial infarction in the drug group. So I think it is reasonable to conclude that anticoagulant therapy has no significant benefit in the prevention of cardiovascular events. No need to keep reinventing the wheel.
If someone has calcifications on a CAC scan, do you consider them to have heart disease? I know you don't like the test, but wondering what you do with the results. Does the presence of calcifications change a patient from primary to secondary prevention? This could make a difference in the aspirin recommendations.
Since no one has responded to your question, I'll put my two cents in and say no, calcifications are not evidence of heart disease. I think Dr. Mandrola's dislike for the test is precisely because we don't know what the results mean. Why do some people with atherosclerosis develop calcifications and others don't? Who knows? Might the calcifications protect the arterial intima from rupture rather than make it more likely? Nobody knows. What is certain is that multiple studies have shown that aspirin has no significant effect in preventing myocardial infarction or other cardiovascular events in either primary or secondary therapy.
I appreciate you responding. My understanding is different. While the relationship between CAC and plaque susceptibility is not completely understood, the presence of CAC is direct evidence of the presence of coronary atherosclerosis. This seems universally agreed upon in the litterature. What to do about it is another question.
I would recommend the following by the father of Aspirin studies. This man is very convincing.
Prof Peter Elwood FRCP (b. 1930) was a member of the scientific staff of the Epidemiological Research Unit (South Wales) from 1963 and its Director from 1974 until its closure in 1995. He qualified in medicine at Queen’s University, Belfast, in 1954 . He is currently Honorary Professor at the Institute of Primary Care & Public Health, University of Cardiff.
I think it's a simple discussion between doctor and low dose aspirin patient. Whether a patient has had observed bleeding or coagulation issues while on low dose aspirin from cuts or other injuries that caused bleeding. I've had that discussion with my doctor.
Maybe in this meta analysis we are seeing the (already known) effect of ASA in diabetic patients included in ASCEND, but having only patients with low risk of ASA related bleeding (tolerance had been “tested” in a sort of run in period before inclusion). I don’t think this MA should inform practice until the deprescription trial is run.
Check their Lipoprotein(a). If high, they need to be on aspirin.
It would be interesting to see whether there are differences in primary prevention with aspirin for people who are genetically predisposed to increased blood clotting/thrombosis based on a polygenic risk score...I consult for a company offering consumer genetic testing and I see plenty of people having a higher than average risk for increased blood clotting/thrombosis, with or without other genetic predispositions, but very often accompanied by an increased risk of CVD. (I am not referring here to people with Factor V Leiden mutation, as it is more rare). Any ideas or resources?
Aspirin for primary prevention has been back and forth just in the past 20 years alone.
Coming out of residency, I remember that the advice was 81-160 mg aspirin for any man over 40...
Medical reversals...
The question I would have is when one says increase in bleeding, what does this mean. Is it a clinically relevant bleeding event?
Was the aspirin immediately stopped, or titrated down...? Could that make a difference?
Aspirin was stopped abruptly for all the studies I remember where people already taking aspirin were randomized to the placebo group. I know that some people have referred to a rebound effect to abrupt discontinuation but I have never seen any evidence for that. It seems unlikely that would occur given the nature of the effects of aspirin on platelets. Aspirin has a half-life of only about 20 minutes in the circulating blood. It is very quickly metabolized to salicylate which has none of the platelet inhibiting effect. Aspirin will inhibit aggregation of a portion of the platelets in the blood during the period of aspirin activity and this is irreversible during the lifetime of the platelets (about 8-9 days). But the bone marrow is creating billions of new platelets every day and these will not be affected by the prior aspirin dose. Hence the need for daily dosing in order to maintain the desired effects.
On the one hand, looking at a retrospective subgroup with a trial that was negative on the primary endpoint seems like a no-no on first principles.
OTOH, “primary prevention patients already on ASA who have not bled” does maybe select for a plausible subgroup that stands to reap the future benefits of ASA in primary prevention while having an already- demonstrably lower bleeding risk.
As opposed to “starting” ASA for primary prevention, where the answer is clearly no, perhaps de prescribing should be guided by pt preference. Not one size fits all, it would seem. Hopefully better data will be forthcoming (altho not sure who would pay for such a study).
Excellent point. The retrospective subgroup analysis is a favorite trick of the epidemiologists in order to claim some significance for their research. They will point out that females between the ages of 30 and 40 who are non-smokers of Norwegian descent and eat brussel sprouts daily have a lower/higher incidence of disease X than others. I think one of the early examples of this was the Framingham Study---one of the most over-rated ever. They were determined to find a correlation between cholesterol levels and heart disease but, unfortunately, it didn't pan out. They then broke down the data further and discovered that there was a correlation (albeit a weak one) for males under the age of 50. Unfortunately zero correlation for males over 50 and females of any age.
But the rest is history.
It’s always the Brussel sprouts……and Scandinavians
Aspirin withdrawal itself causes a rebound and that could also bias the results.
FYI one observational study finds aspirin with fish oil is associated with increased death. There's a non-obvious interaction.
In those with heart disease from what I can tell the limited number of studies that use very low doses like 20 mg of aspirin look like it may work almost as well. 81 mg seems to be incidental instead of optimal.
Modern medicine needs to get wise to nattokinase. Recent retrospective study found like a 30% reduction in carotid plaque among other good things. Even more if combined with aspirin. No reported side effects. I have a couple concerns but it probably beats the crap out of everything else.
I was hospitalized with a perforated ulcer which was exacerbated by taking aspirin as it caused severe damage to my stomach lining. If the benefit is minimal, I would say skip it. Thanks for the post. It seems doctors rarely admit when they are wrong. sabrinalabow.substack.com
I disagree with the statement that this is a tough call. Clearly there is no benefit in taking daily aspirin in patients without a history of cardiovascular disease. The absolute risk reduction in the major end points for ASCEND was 1.1%. For ARRIVE 0.19%. ASPREE showed a difference of 0.6 events per 1000 person-years. The figures given in the article were obviously Relative Risk Reductions and , therefore, extremely misleading when dealing with these low rates of event occurrence. The British Medical Journal reported a "Collaborative Overview of Randomized Trials of Anti-Platelet Therapy" in 1994 that combined the results of 174 trials using low dose aspirin or other platelet inhibiting drugs. These involved various different categories of patients---with or without CV disease. The results were remarkably similar to those reported in the article---1.1% reduction in total mortality and nonfatal myocardial infarction in the drug group. So I think it is reasonable to conclude that anticoagulant therapy has no significant benefit in the prevention of cardiovascular events. No need to keep reinventing the wheel.
Oh just what I needed to be even more confused
If someone has calcifications on a CAC scan, do you consider them to have heart disease? I know you don't like the test, but wondering what you do with the results. Does the presence of calcifications change a patient from primary to secondary prevention? This could make a difference in the aspirin recommendations.
Since no one has responded to your question, I'll put my two cents in and say no, calcifications are not evidence of heart disease. I think Dr. Mandrola's dislike for the test is precisely because we don't know what the results mean. Why do some people with atherosclerosis develop calcifications and others don't? Who knows? Might the calcifications protect the arterial intima from rupture rather than make it more likely? Nobody knows. What is certain is that multiple studies have shown that aspirin has no significant effect in preventing myocardial infarction or other cardiovascular events in either primary or secondary therapy.
I appreciate you responding. My understanding is different. While the relationship between CAC and plaque susceptibility is not completely understood, the presence of CAC is direct evidence of the presence of coronary atherosclerosis. This seems universally agreed upon in the litterature. What to do about it is another question.
Yes, many questions.
The first is what distinction might be made between anti-inflammatory properties and anticoagulant effects.
I would recommend the following by the father of Aspirin studies. This man is very convincing.
Prof Peter Elwood FRCP (b. 1930) was a member of the scientific staff of the Epidemiological Research Unit (South Wales) from 1963 and its Director from 1974 until its closure in 1995. He qualified in medicine at Queen’s University, Belfast, in 1954 . He is currently Honorary Professor at the Institute of Primary Care & Public Health, University of Cardiff.
https://www.youtube.com/watch?v=7mOvJbmpG6A&list=TLPQMDEwMTIwMjTxEHOJPyDgmg&index=4
I think it's a simple discussion between doctor and low dose aspirin patient. Whether a patient has had observed bleeding or coagulation issues while on low dose aspirin from cuts or other injuries that caused bleeding. I've had that discussion with my doctor.
The idea of universal prophylaxis has always seemed strange to me
Maybe in this meta analysis we are seeing the (already known) effect of ASA in diabetic patients included in ASCEND, but having only patients with low risk of ASA related bleeding (tolerance had been “tested” in a sort of run in period before inclusion). I don’t think this MA should inform practice until the deprescription trial is run.