Time Stamps

  • 02:53 Guideline recommendations 
  • 07:00 How does Aspirin work? 
  • 09:11 Trial Data
  • 13:00 ASCVD Risk Calculator
  • 18:07 Starting vs. Stopping Aspirin 
  • 22:11 Summary 

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Show Notes

Q1: “Have you been getting questions about aspirin?” 

  • Patients are hearing about aspirin from a variety of sources differing drastically in credibility: USPSTF? The NY Times? Friends and family? 
  • As clinicians practicing evidence-based medicine, what is our best approach to educating patients about aspirin? 

Q2: “What do the guidelines say about aspirin’s role in primary prevention?”

  • ACC/AHA guidelines (2019):
    • For patients aged 40-70 years, aspirin should be used infrequently for primary prevention [Class IIb recommendation]
    • For patients aged >70 years, the evidence does not support the use of aspirin for routine primary prevention [Class III recommendation]
  • USPSTF guidelines: 
    • For patients aged 40-59 years with a 10-year ASCVD risk >10%, starting aspirin for primary prevention should be discussed as a shared decision (grade C)
    • For patients aged >60 years: do not initiate aspirin for primary prophylaxis (grade D)

Q3: “Why and how does aspirin work?” 

  • Prelude: Atherosclerotic Progression
    • Lipoproteins get stuck in vulnerable parts of blood vessel walls, leading to inflammation 
    • Macrophage infiltration, fibroblast proliferation, and continued development of fatty atheroma and fibrous cap 
    • Aspirin mostly* does not exert its effects here 
  • Climax: Plaque Rupture 
    • Chronic weakening of the fibrous cap extracellular matrix by infiltrating macrophages 
    • Rupture of the fibrous cap due to mechanical shear leads to exposure of the necrotic lipid core, attracting platelets 
    • Platelets and fibrin aggregate to form a thrombus, occluding the blood vessel 
    • ** Aspirin exerts its effects by inhibiting platelet activation and aggregation at this step
  • For the average primary prophylaxis patient, more emphasis should be placed on controlling the progression of atherosclerosis > inhibiting platelets in the unlikely setting of plaque rupture

Q4: “What does the latest evidence on aspirin really show us?”  

  • ASCEND Trial (2018)
    • Population: Adults aged >40 years with diabetes but not CVD
    • Parameters: RCT, 100mg aspirin versus placebo, followed for 7.4 years
    • Outcomes: Aspirin group experienced a 1% ARR in CV events but 1% increased risk in major bleeding, translating to a negligible net benefit
  • ARRIVE (2018)
    • Population: Men>55 years and women >60 years with average CV risk 
    • Parameters: RCT, 100mg aspirin versus placebo, followed for 5 years
    • Outcomes: Similar low CV event rates between the aspirin (4.3%) and control group (4.5%)
  • ASPREE (2018)
    • Population: Adults aged >70 years without CVD 
      • African Americans and Hispanic Patients → over > 65 years 
    • Parameters: RCT, 100mg aspirin versus placebo, followed for 5 years
    • Outcomes: Similar low CV-related mortality rates between the aspirin (1%) and control group (1.2%)
    • Caveat: 0.7% higher rate of all-cause mortality in the aspirin group compared to control group, driven largely by a paradoxically higher rate of colorectal cancer deaths
  • USPSTF Meta-Analysis (2022)
    • Includes all three trials discussed above as well as prior data
    • Conclusion: Aspirin use is associated with a reduction in CV events with an OR of 0.90 (CI 0.85-0.95), and an increase in total major bleeding with an OR of 1.44 (CI 1.32-1.57).
      • However, aspirin had no statistically significant impact on CVD-related mortality or all-cause mortality

Q5: “How should we approach individualizing aspirin decision-making?”

  • A seemingly easy way out → 10-year ASCVD Risk Calculator 
    • Helps synthesize and quantify data but is less generalizable than most clinicians realize 
    • Does not capture a variety of key risk factors: Smoker pack-year history? Family history of CVD? Obesity? Chronic inflammatory diseases? Coronary Calcium Score (CAC)? 
  • What are some particular risk factors that I should consider?
  • What are some reasons to continue or start aspirin? 
    • Presence of secondary prevention indications (CAD, CVA, PAD)
    • Presence of uncontrollable/refractory traditional risk factors (Ex. can’t quit heavy smoking, can’t control BP etc.)
    • Presence of non-traditional or unmeasured risk factors not accounted for by traditional calculators
  • Who should start aspirin is a slightly different conversation than who should continue aspirin
    • Patients who are tolerating long term aspirin without bleeding complications are, on average, good candidates for continuing aspirin. 
    • For patients looking to start aspirin, the recent evidence shift in benefits/harms is more nuanced to balance and requires individualized risk assessment. 
    • Ultimately, know that the majority of patients will be OK regardless of the final decision on aspirin alone.
  • Summary: Shared decision-making on aspirin for primary prevention is much more nuanced than the ASCVD calculator can elaborate. Taking a robust history, understanding each patient’s risk tolerances, and utilizing new tools such as Lp (a) and CAC are all good ways to individualize this decision. However, proper management of known, modifiable risk factors remains the centerpiece of ASCVD prevention. 


Cary: Hi, I’m Carrie Blum. I’m a primary care doctor. 

Greg: I’m Greg Katz. I’m a cardiologist and also like to think of myself as an internist. 

Cary: Welcome to Mind the Gap on aspirin for primary prevention. 

Greg: So today we’re gonna talk about a few things. First, we’re gonna talk about what the recent guidelines tell us about aspirin for primary prevention. We’ll go through the data that inform those guidelines, and then ultimately we’re gonna decide who really benefits for aspirin therapy. So the amount of questions that I hear from patients about aspirin is honestly kind of insane. I hear questions about news reports. I hear questions about changing guidelines and especially after the USPSTF updated recommendations came out, the number of just sheer questions I was getting from patients who had been on aspirin or who had never been on aspirin about, Should I start? Should I stop? Does this mean aspirin doesn’t have a role in cardiovascular disease? I just read this in the New York times… It’s just been one thing after another and it’s constantly the sort of topic that my patients are interested in learning about.

Cary: Yeah. And you know, that media sort of message gets filtered and sort of pass through a lot of different middlemen. I have patients telling me how my cousin told me to stop my aspirin. Sometimes those are patients that even have a very compelling indication to be on it. So long story short, I think that we’re both getting this a lot these days. 

Let me just remind us what the ACC and AHA say about aspirin for primary prevention and then we’ll move on to the newer USPSTF guidelines. So first of all, the ACC/AHA these coming back from 2019 and they basically have a class 2B recommendation for adults, age 40 to 69, saying aspirin should be used infrequently for primary prevention. And specifically in those patients who are high risk for cardiovascular disease, but low risk for bleeding. Whereas for patients 70 and older, it’s a class three recommendation, meaning no evidence or evidence does not support its use.

Greg: Why don’t you tell us a little bit more about the USPSTF guidelines? 

Cary: So the U S preventative services task force actually came out with their newest set of guidelines just this year. And they say that adults age 40 to 59, who have a greater than 10% 10-year ASCVD risk. They could start aspirin. They give it a C. So our favorite score, which basically ultimately means it’s going to be a shared decision between patient and provider. 

Greg: Not that all decisions are not shared between patient and provider…. that’s what I found confusing about this update. 

Cary: I hear ya. I mean, really ultimately they should be, but the way I interpret this is there’s really, it could be reasonable to go either way from the standpoint of risks and benefits. And so when you’re in that gray area, I think more talking can often be helpful to find the right decision. And you know, they also put their cutoff lower. The interpretation is, do not initiate aspirin for primary prophylaxis and adults over 60. 

Greg: Yeah. And I think that that’s an important point  to emphasize is that all of these guidelines are for primary prevention. They’re not for secondary prevention and that’s a concept that’s not super familiar to a lot of our patients. And so for the purposes of this discussion, for the purposes of how we’re framing this for our patients, when we talk about primary prevention, what we’re really talking about is somebody who’s never had a heart attack or stroke. 

Cary: Right. And I think we might be able to also include peripheral artery disease, patients with known triple A’s. Intermittent claudication probably would put in that category as well. 

Greg: Yeah. I think that that’s reasonable, you know, PAD in every kind of atherosclerosis study connotes a higher risk of all adverse cardiovascular events. And so it’s certainly fair to put them in a higher end group … where that line exists between primary and secondary prevention, I think is very, very gray. And it’s not like every study that was done did all of the testing that you would need to do in order to assess whether somebody had the  presence of PAD or had a high coronary artery calcium score… any of the other things that we would use as kind of like soft cutoffs, when we’re thinking about the primary versus secondary prevention, gray zone that exists.

Cary: It’s interesting that both of these guidelines specifically recommend against aspirin for older folks. My first thought is they’re older.. they should be higher risk… they should be on more medications. But the fact that we’re talking about them as a primary prevention group, connotes the fact that they have not had an event and sort of by definition may make them a lower risk group to begin with. So it may not be such a simple, older equals high risk calculation when you’re talking primary prophylaxis. 

Greg: Yeah, that’s an interesting way of framing it. This idea that, well, if you’ve made it to age 70 and you’ve never had an event, then you’re almost like an escaper of chronic disease and maybe the same way that atherosclerosis risk increases with age doesn’t necessarily apply to you. I’m not a hundred percent sure that I fully buy that logic, but I do think that there’s something to the fact that the older you are, the more, not just bleeding risk exists, but the more catastrophic, even sort of smaller bleeding events can be when it comes to your clinical course. But the recommendations are consistent across all the guideline groups that the older you are, the less role that aspirin has in primary prevention. 

Cary: So we all learned probably even before medical school, that aspirin prevents MIs. But you know, how does that actually work? Like what’s the pathophysiology there of how aspirin helps to stop heart attacks?

Greg: Yeah, so aspirin does prevent heart attacks, and it does that because of its role blocking the function of platelets. If you inhibit platelets, you block thrombus formation and you inhibit the blockage of an artery. But aspirin doesn’t actually affect the progression of atherosclerosis and it doesn’t affect the progression of cardiovascular disease. The progression of atherosclerosis happens when you have atherogenic lipoproteins that get into the blood vessel wall… they cause inflammation and then you have foam cell formation and plaque development. The only time that aspirin’s playing a role there is when those plaques that have formed rupture and they cause a blood clot to form. And so that’s aspirin’s role. It’s really at the end stage of atherosclerosis. If you talk to a platelet biologist, they will tell you probably more than you actually wanna know about the ways that activated platelets accelerate atherosclerosis. And if you look at disease states with activated platelets like Lupus or HIV, there is certainly an association between platelet activity and the progression of cardiovascular disease. But for the majority of people that activated platelet leading to furthering of the atherosclerotic disease process is a second or third order issue. It’s just not really a big deal for most of us. And so aspirin prevents heart attacks in the average person because if a plaque were to rupture, it reduces the likelihood that a thrombus is going to develop and lead to an ischemic myocardium. 

Cary: Greg. You know, honestly it’s kind of a relief to hear you say that because now when I’m talking to patients, I don’t have to go back to square one and pretend that I understand how aspirin is affecting plaque development. It really seems to work right there at that final moment during rupture to help prevent mis from becoming worse. Am I thinking of that right? 

Greg: You’re thinking of it exactly right. It’s not modifying atherosclerosis, it’s just reducing the likelihood that plaque rupture leads to thrombus formation.

Cary: Greg we talked about the guidelines. We talked about how aspirin works. Now I know that those new guidelines must have come from somewhere. I know that there’s some new data out there. Can you help walk us through, some of the new big trials in aspirin for primary prevention? And help to summarize sort of where we stand now compared to before the guidelines. 

Greg: Yeah. Let’s rewind the clock to early 2018. The recommendations at that point were weakly in favor of aspirin for primary prevention. And I think that most cardiologists and probably most internists at the time when asked by a patient would have probably said, yeah, you know, I think aspirin is probably beneficial in the aggregate and I don’t really see that much of a reason why you shouldn’t be taking it. And you know, that comes from old data that shows, a very small, absolute risk reduction in vascular events with the use of aspirin. But then mid 2018 comes around and we get ASCEND, ARRIVE and ASPREE and these three clinical trials are what changed the guidelines and change the USPSTF recommendations. And so ASCEND looked at adults with diabetes, but no established cardiovascular disease. They gave them 100 mg of aspirin versus placebo, and they saw an absolute risk decrease in vascular events of about 1% and an absolute increase in major bleeding by about one percent that net benefit is essentially zero. We also have ARRIVE. ARRIVE looked at adults over the age of 55 for men and 64 women who had average cardiovascular risk. And again, aspirin versus placebo, these patients had a really low event rate and no statistically significant difference between the two groups in terms of vascular events or in terms of negative consequence. Then we also have ASPREE. ASPREE looked at adults over 70, who didn’t have cardiovascular disease. and they randomized patients to a 100 mg of aspirin versus placebo. Five-year follow-up this tiny, tiny event rate, and it was not statistically significant for cardiovascular disease. What was weird about a spree is that there was a higher rate of all cause mortality in the aspirin group, which was driven by largely by an increase in colorectal cancer. Mechanistically it was really perplexing to a lot of the researchers looking at this because there are all these hypotheses about how aspirin would actually reduce colorectal cancer risk.

Cary: Correct me if I’m wrong, but I think the most recent version of the guidelines, or maybe it was the one before that they actually had colon cancer risk reduction as one of the indications for aspirin, right alongside cardiovascular risk reduction. So that’s really turning that whole script on its head…

Greg: Yeah, I’m not sure that we can really draw the conclusion that aspirin makes you die from colon cancer, which if you read ASPREE, literally is the direction that you would go, but it certainly raises the question of whether the biological plausibility of aspirin reducing colorectal cancer risk has any sort of role in the actual reality of taking care of patients.

Cary: So thanks for walking us through those three big trials, Greg. But, because like I’m not able to internalize that much at one time. Can you just summarize for me the big takeaway points?

Greg: So Carrie, you have these three trials in 2018 ASCEND, ARRIVE, and ASPREE, and the absolute, most optimistic reading of the sum total of this data is that in high-risk primary prevention patients, aspirin reduces cardiovascular disease risk a little bit and increases bleeding risk by about the same amount and a less optimistic reading of this data would say that aspirin basically does nothing for anyone. 

Cary: So let’s just assume our patient’s already taking a stab. Right? And they’re coming in. They want to have this conversation about aspirin. So we just plug numbers into a calculator and let that decide for us.

Greg: Cary you, you are way too thoughtful to just plug numbers into a calculator. And so I like, I’ve heard you talk about the flaws of ASCVD risk stratification before. And so, when you’re looking at these calculators, who do you think doesn’t actually fit into them?

Cary: So I realized our listeners couldn’t see me, but I was saying that with a smile on my face, you know, I do plug numbers into a calculator, but I do it with a grain of salt. No, I hear what you’re saying, Greg. I think. The approach to starting aspirin for primary prevention needs to be an individualized approach that may or may not start with the use of a calculator, just to sort of get a sense of where your patient is. Do you use them at all, Greg? 

Greg: The answer to that is occasionally, but less and less. And part of the reason for that is as you use it more, you internalize a lot of the metrics and you start to just kind of seamlessly incorporate them into the way that you’re thinking about a patient. And so the classic risk factors, age, blood pressure, blood sugar, cholesterol but there’s a lot of patients that get missed by these calculators because they’re not as personalized. They don’t look at all of the specifics that maybe you and I would talk with our patients about. So they don’t talk about how much does somebody smoke? What is their family history? Did everybody have bypass surgery before they were 55 years old? Did the patient have a chronic inflammatory disease? None of the risk calculators incorporated lipoprotein (a), they don’t incorporate chronic kidney disease, and so, it’s not that the risk calculators aren’t good… it’s that some of our most vulnerable patients actually fall through the cracks when you’re using the risk calculator approach. 

Cary: Yeah, and this comes up clinically all the time. Like I can think of a specific patient who I had, who had a history of smoking, but quit a while ago, early heart disease in some family members. She was otherwise asymptomatic. She had a CT scan of her lungs for PE rule out and ultimately was found to have some coronary calcifications and had a very high coronary artery calcium score. But if you put her numbers into the calculator, I think it actually came out with a 0.3% risk of cardiovascular disease over the next 10 years. So that patient, I think provides a really good example of how the calculator really doesn’t work well for everybody. Maybe it’s a good place to start. But there’s so many things that they don’t even ask, right? They don’t ask about family history. The don’t count smoking history if it’s very remote. There’s a lot of medical history that may predispose to coronary artery disease, such as chronic inflammatory conditions that are not accounted for. And so I think my evolution on the calculator has also been to use it less and less. I think when I was a resident, I was tempted to sort of see that there was an algorithm that would tell me what the right thing to do. But it’s becoming more and more clear that algorithmic approaches. Appropriate for an individual with a lot of different factors, not only from their own medical history, but from their own set of values that need to be accounted for. 

Greg: Yeah. And when it comes to how to incorporate the calcium score, you know, there’s a calculator using the MESA database, which is the multi-ethnic study of atherosclerosis where you can actually plug in somebody’s risk factor plus their calcium score and you can get an estimated risk both with and without the calcium score. So it can be helpful in thinking about how somebody is reclassified by the calcium score. But at the end of the day, what you’re trying to do is identify the vulnerable patients so that you can give them a different therapy than you give to everybody else. The biggest one for me is really poorly controlled diabetes or just like really catastrophic metabolic syndrome. And so I’m always looking at that triglyceride to HDL ratio on a lipid panel and the higher that number is the higher that ratio of triglycerides to HDL cholesterol. The more likely somebody is to be just super insulin resistant, even if their pancreas is able to pump out enough insulin so that they don’t become frankly, hyperglycemic. So that’s a big thing to me of the poorly controlled metabolic syndrome patients that I may lean a little bit towards starting aspirin for primary prevention. But I think heavy tobacco use presence of PAD, family history is playing a bigger and bigger role, and then the patients who have a really high lipoprotein (a) especially in the presence of a family history are some of the folks that I’m going to start recommending, or that I’m going to continue recommending aspirin for primary prevention.

Cary: All right, so I think what I’m hearing, Greg, is when we’re deciding who to start aspirin on, we should pick our patients who are at particularly elevated risk, and that includes folks with chronic inflammatory diseases, active smoking, peripheral artery disease, and diabetes. Those are the people that we should really be targeting to start aspirin for primary prophylaxis.

Cary: Here’s another question, Greg, let me ask you something about starting versus stopping aspirin because a lot of patients who come in are kind of already taking aspirin. And the question is, should I stop? The guidelines that were just recently published specifically do not speak to that population. And the guidelines actually are answering the question of who should start aspirin for primary prophylaxis. Is that a different question or is that really the same question? 

Greg: I think at the end of the day, the decision about starting versus continuing is very, very similar to me. And you can make the argument. You know, well, if you’ve been on aspirin for 15 years, maybe it’s only primary prevention because aspirin has prevented a heart attack. I don’t know that that’s the case, but I also don’t know how you assess for that versus the patient who’s just lucky enough that they didn’t have a GI bleed and they weren’t going to have a heart attack anyway. It’s a really, really hard thing to figure out, but you know, if you’ve been on aspirin for a long time, it’s suggested you tolerate it fairly well. 

Cary: Fair enough. I sort of use that. I also use the fact that they’ve already proven themselves to be somebody who’s interested in taking medication for preventive purposes as a sign that I probably err on the side of continuing medications for prevention. If they haven’t really heard about the harms though, I’ll usually use that as an opportunity to talk about this as a real medication that carries with it, both benefits and harms. And a lot of times I can see the wheels turning in their head and by the next time they come in, they’re sort of wanting to have a conversation about stopping. 

Greg: Yeah, I think clinical inertia is powerful in both good situations and in bad ones. 

Cary: Fair enough. I’m always trying to remind my residents, you know, that just because something looks good now doesn’t mean we should keep it that way. You never learn new things until you try new things. And so I think going ahead and taking a stab at stopping aspirin, even if you know, the patient had been doing well on it, if you really think that’s the right thing to do for the patient is the right thing to do ultimately. 

Greg: And you know, I really think at the end of the day that most of our patients are going to do fine. Whether we continue aspirin, stop aspirin, start it, or don’t start it. And. Way that I kind of synthesize all of this data from our meta analyses, from ASCEND, ARRIVE, ASPREE it’s aspirin has a small absolute impact on lowering the risk of cardiovascular events. And it comes at a small risk of increased bleeding. And if you just think about it very, very simply from that 30,000 foot view. The decision about what to do is something that you can have a normal conversation with a patient just kind of like person to person and come up with a decision about which risk do you find more tolerable to take. And that’s kind of where I’ve landed with. A lot of this is that if we can have a conversation in plain English and maybe it’s grounded a little bit in what, what your estimate estimated risk is via one of the, the risk calculators, but at the end of the day, if we can have a regular conversation about which risks do you prefer taking? I think that it’s it’s the sort of thing where we land on that that class C or that grade C recommendation from the USPSTF task force, which is, this is a shared decision between patients and their doctors. So it, I kind of come back to this idea that aspirin is a decision for primary prevention that probably isn’t going to have much benefit, and it’s probably not going to have that much harm. as long as you’re thinking about it, from the perspective of either a small, absolute benefit or a small absolute risk, and then you’re using clinical characteristics to modify where you think the risk benefit analysis lands. I think that you’re doing the right thing for your patients in that sense. 

Cary: Cool. Yeah, I think that’s a great way to summarize Greg so I think that we’ll keep doing what we’re doing. I hope that our listeners were able to pick something up from this conversation. If I may let me just sort of circle back and try to summarize a little bit from the top.

So you know, patients are starting and stopping aspirin. They’re asking us, they’re not. It’s all based on these new guidelines from the USPSTF, which give a C grade meaning shared decision for aspirin, for primary prophylaxis for adults, age 40 to 59, whereas for 60 and up grade D do not initiate you know, the question of aspirin for primary prophylaxis, it should probably start with a close and careful examination of whether this patient really is in that primary prophylaxis world. Have they ever had an event that would put them into secondary? If not, check that they’re on a statin. Those drugs have so much more benefit than aspirin, and if they are on a statin, then you can probably move on to the aspirin decision. Have a little bit more of a nuanced understanding of what puts this patient at risk or not more than just the calculator. I think that we can do better than that and try to either identify patients who have both unmeasured risk factors and risk factors that are very difficult to control despite our best efforts. And those patients are probably the ones that we would put on aspirin as long as they’re not having very high risk of bleeding.

Greg: I would just add one more thing, which is that our patients are probably going to do fine regardless of what we decide. 

Cary: So maybe we didn’t even need to do this podcast when we come back and do another one with me, I’ve seen a lot of headlines recently about how HDL is actually bad, which, you know, it makes me wonder about your whole triglycerides over HDL ratio.

Greg: I’m obsessed with lipid panels that I can’t wait to talk about them more.

Cary: Well let’s do it. Let’s make a date.

Greg: All right and that’s it for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us. Please tweet us and leave us a comment on our website, Instagram or Facebook page.

Cary: Thank you, Yichi Zhang for the audio editing. And Lizzie Holland for the accompanying graphic. As always, we love hearing feedback, so email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

Greg: This podcast is for general informational purposes only. Listening to this podcast does not constitute the formation of a doctor patient relationship, and nothing that you heard should be construed as personalized medical advice.


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