Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 97 I'm your co host, Dr. Kane, Speaker 1 00:35 and I'm Dr. Patel. And to our listeners, we have a sad news. Dr. Michael Schuman has departed the university and moved on to other opportunities in Kentucky, so he won't be our regular contributor. However, you will hear His voice we promise as guest speaker, because he's very much interested in talking to our listeners, Dr. Sean Kane 00:56 moving forward today, talking about the title ASPREE, ARRIVE, ASCEND, making an acronym soup for aspirin and Dr. Patel. It sounds like today we're talking about the use of aspirin for primary prevention, specifically focusing on some newer literature out there. Speaker 1 01:11 Yeah, it's been quite a bit of undertaking on understanding whether there is good evidence for aspirin and primary prevention. We know that there is clear benefit in secondary prevention, but the position on primary prevention has been tipping, and that's through a lot of different literature that's been out, and the three acronyms that you mentioned Dr. Kane, they were randomized, controlled trials published last year that actually compelled some of the governing organizations like AHA and ACC to update their recommendation. So in a nutshell, that's what we're going to discuss today, Dr. Sean Kane 01:48 and just for complete clarity, when we say primary prevention, that means using aspirin in someone who's never had a heart attack or a stroke, versus secondary prevention and someone who has had a heart attack and a stroke, and you're trying to try to prevent a second one from Speaker 1 02:01 happening, absolutely, and that's correct, and it's good to make that distinction when you are evaluating a patient in front of you. So Dr Dr. Sean Kane 02:08 Patel, can you kind of set the stage here with a case of a patient to kind of give the audience a typical patient where this scenario comes up? Speaker 1 02:17 Sure. I mean, I've gotten a lot of such question, but let's hear a case. We have a 66 year old male with past medical history of hypertension, stage 2 CKD, and recurrent VTE who is on lisinopril 40 mg daily, warfarin 4 mg daily, with a TTR of about 72% over the last 3.5 years. And he's also taking aspirin, 81 mg daily. He doesn't have any personal or family history of ASCVD and denies any current or past use of tobacco products. He tells us that he did, however, have a hospitalization about five months ago where he had a GI bleed and needed 2 PRBC transfusions; there have been no bleeds since then. And blood pressure is well controlled, and we measured it in the office today, being 126 over 72 and pulse of 82 and so he's really the question is that he listened to Good Morning America, and there were, they were talking about some updates and aspirin recommendation, and wonders whether he needs to continue his aspirin or not. So that's the stage we're setting up, and let's take a look at more details on aspirin to begin with. Dr. Sean Kane 03:25 So really, you know, aspirin is an NSAID, right? So it's an NSAID, just like all of the other NSAIDs, like ibuprofen and naproxen, we actually just did kind of a large review on that topic. But aspirin is unique in that it's a COX-1 and COX-2 inhibitor. So it is inhibiting this enzyme that produces different compounds, including thromboxane A2, and thromboxane A2 is the thing that makes platelets stickier. So effectively, aspirin is covalently binding to COX‑1 in this case, and that covalent binding makes it so that you don't make the compounds that make your platelets stickier. Speaker 1 03:57 Yep, and this binding is irreversible, so basically, you have to wait it out for the lifespan of platelets, which is seven days for the therapeutic effects of aspirin to go away. And this is where we use aspirin. This is how we use aspirin to prevent clots in the blood vessels and the reduction of the atherosclerotic risk. We call it. Dr. Sean Kane 04:18 Now when I think about aspirin dosing, I always think about like the baby aspirin, which is probably the worst name for an aspirin dose, given that we don't give aspirin to children at all. But baby aspirin being in the US, 81 milligrams per day. Are there other doses that are out there? Speaker 1 04:33 Dr. Patel, sure. European Studies love to use 100 milligram, because that's the dose available in Europe market. So some of the new studies that are out, and especially if they're multinational, you'll see a range of low dose aspirin reported. We're going to, in a bit, talk about some historical perspective on where we stand as far as recommendation, and we'll elaborate more on what their quote, unquote low dose ranges are. But let's just say, generally, in us, we're talking about 81 milligrams. Yes, and so for prevention, 81 milligram is generally used, with some exception for secondary prevention, where the higher dose is used. But we're talking about primary prevention here today, and we know that higher dose of 325 milligram is not better than lower dose. What we do see is higher doses are associated with higher bleeding risk. Dr. Sean Kane 05:20 And specifically, when we talk about bleeding, one of the big issues with bleeding we think about is GI bleeding. Because not only are you having this anti platelet effect, but the compounds that COX‑1 produces are important to maintain the mucosa of your stomach. So if you block that protective lining of your stomach, not only are your platelets less sticky, but now you've gotten rid of this protective lining that COX‑1 was providing to you. Speaker 1 05:48 Yeah. And as we talk about these trials, we are going to talk about the bleeding risk that the trials have, you know, brought forward. But think about it, both of these doses, 325 milligrams or 81 milligrams, are available over the counter. So some of these patients who come to you now are not necessarily taking aspirin because their healthcare provider told them to take it. They're taking it just because their friends taking it, their family member is taking it, and they just feel like it's readily available. So the use of aspirin doses, whether high or low, are higher than necessary in the market, just because of there is no sound clinical judgment behind it. Dr. Sean Kane 06:26 And if you think about it, like, if you were to take aspirin as an analgesic, you're gonna pump that dose up almost to, like, 1000 milligrams, depending on your indication that you're Speaker 1 06:35 looking at Absolutely and we didn't even, we're not even gonna talk about the analgesic doses, but that's absolutely true. Patients have that available over the counter, too. Dr. Sean Kane 06:43 So my favorite response when someone asks about aspirin for primary prevention is kind of like the Facebook status of it's complicated. You know, it really is complicated, and it has been complicated for quite a while. So Dr. Patel kind of walk us through some of the history of guideline recommendations with respect to aspirin as primary prevention. Yeah. Speaker 1 07:02 So we had studies going as far as 1989 but the studies that came somewhere between 2001 and 2014 didn't really show robust CV benefit for add in aspirin. And so looking at those trials, the USPSTF (U.S. Preventive Services Task Force) in 2016 developed this recommendation. And this, if you look at literature, it's been heavily cited the USPSTF 2016 recommendation. And so, in a nutshell, what they recommended is use of 81 milligram aspirin daily. And there was a level B evidence for patients who were of age 50 to 59 with the 10 year cardiovascular disease risk of greater than 10% again, they also wanted to make sure these patients were not at increased bleeding risk, that they had life expectancy of at least 10 years, and that they were willing to take low-dose aspirin for at least 10 years. So we are talking about shared decision making involving patients personal choices here as well. Dr. Sean Kane 08:06 So in the fifth decade of life, you said level B evidence. I assume that we have other levels for different age groups in Speaker 1 08:13 correct so it was a level C evidence for, again, same type of CV risk 10% or above, but it was for 60 to 69 year old patients, and when it came to patients younger than 50 or older than 70, there was just not enough evidence available to make any recommendations for those patients. Dr. Sean Kane 08:31 So again, to reiterate, in 2016 we basically said if you're between 50 and 69 and you have an elevated cardiovascular risk for primary prevention, you may consider aspirin, but the level of evidence isn't great, and beyond those age groups of 50s to 60s, we just didn't have a lot of data to support a specific recommendation. Speaker 1 08:50 And then, besides the Preventative Task Force, we have other organization that weighed in. So we have the CHEST guidelines. The 2012 guidelines from CHEST said you can grade 2B evidence for patients 50 years or older to use low-dose aspirin. Again, this definition was 75–100 milligrams daily. Looking at our patients with diabetes, American Diabetes Association in 2018 said it was Level C evidence for men and women with diabetes ≥50 years of age with one or more risk factors, and those risk factors were either family history of premature cardiovascular disease, hypertension, dyslipidemia, smoking or albuminuria. And again, these patients had to be not at higher or increased risk of bleeding. And this dose range was 75 to 162, milligrams daily. I think Dr. Sean Kane 09:42 that's interesting. So just looking at the last three organization guidelines you mentioned, one says if you're above 50, but less than 70 with an elevated cardiovascular risk. One says if you're above 50, regardless of your cardiovascular risk, and then one says if you're above 50, and then you have some other risk factors, then you could consider it in addition. Into being a diabetic. So I love it when guidelines disagree with each other or have different nuances, because then that gets us away from the mantra of, well, the guidelines say, dot, dot, dot. Then you start thinking about, well, why are there discrepant guidelines? You know what literature exists that may make you push one way or the other, given that typically these guidelines are looking at the same data, right, right? Speaker 1 10:23 And if you think about it, the US Preventive Services Task Force said, 10‑year CVD risk, right? So we know that there is a difference between CVD and ASCVD, where ASCVD includes stroke. So then the Stroke Association came out in 2014 and added their two cents because they didn't think the USPSTF recommendations were encompassing the stroke patient. So they said either 81 milligrams daily or 100 milligrams every other day. Not even sure where this is coming from, right? But Level A evidence for patients with 10 year risk of greater than 10% again, we had to make sure the treatment benefits were outweighing the risk of bleeding. And then they looked at individually for women with stroke prevention as well as patients with CKD, and those were level B and Level C evidences. Dr. Sean Kane 11:15 And then sometimes I like to look across the pond and see, well, what do the Europeans say? Again? They're looking at the same data. What did the Europeans say with respect to aspirin for primary prevention? Speaker 1 11:25 So this is way before the new ASPREE, ASCEND, and ARRIVE trials came out. The European Society of Cardiology had a Level III recommendation. And if you skim through what the level three recommendation means is that do not use it for primary prevention, because the risk of bleeding is higher than the benefits that confers Dr. Sean Kane 11:44 awesome so we literally have a European guideline that has the opposite recommendation of a number of American based guidelines. Speaker 1 11:52 Then right? And then, if you think about all these guidelines, the primary trial literature did not include large numbers of patients on other drugs that also confer ASCVD risk‑reduction benefits, such as statins or ACE inhibitors/ARBs. That was the difference; those drugs have been game‑changers in cardiovascular risk reduction. Dr. Sean Kane 12:19 so then if I was to design the perfect trial, Dr. Patel, that trial would be older adults, because, as we mentioned, above 70 years of age, we just didn't have a lot of data. Potentially, I want a more modern trial that had patients that were taking statins, that had good blood pressure control, something that was more reflective of our current practice, right? So if only we had such a trial, right? Speaker 1 12:42 And also, don't forget the diabetes patients, because they have two fold higher risk of cardiovascular disease, right? So when we talk about these three trials — ASPREE, ASCEND, and ARRIVE — they did just that. They were published in mid to late 2018 and patients were on statins. And if you were to break it down: ASPREE ≈34% on statins, ASCEND ≈75%, and ARRIVE ≈43% on statins. And then, besides these three trials, we'll also look at systematic review and meta analysis that was published in January in JAMA, and then looking at all this evidence, the AHA/ACC updated their guidelines in March, and so let's dive a little bit deeper into what the evidence is. Dr. Sean Kane 13:28 And for the listeners playing along at home, if you want to actually look at any of this primary literature, we'll have links on HelixTalk.com episode 97 and you're welcome to kind of go through and peel through the evidence on your own, knowing that we can only cover so much in a fairly brief podcast, right? Speaker 1 13:44 So first thing first, let's look at the evidence in elderly patients, and that's where the ASPREE trial comes in. It was a robust trial. We are looking at an N of about 19,000 healthy elderly patients. They needed to be at least 70 years old. But African American and Hispanic males were eligible at ≥65 years old, so we had a robust patient population included. There were some percentage of patients with diabetes in here as well, about 11% and the median follow up time for this trial was 4.7 years again, they randomized patients to enteric‑coated (EC) 100 mg aspirin versus placebo. Patients who were excluded were patients who were using other medication that can increase risk of bleeding, such as anti platelets or anticoagulants, patients with BP ≥ 180/105 mmHg, but they did allow short-term use of low‑dose NSAIDs Dr. Sean Kane 14:42 in terms of outcomes. So the primary endpoint was death, dementia or persistent physical disability. There was no difference in that they had a number of different secondary endpoints. One was cardiovascular disease events, and these were actually really similar. So 448 events versus 474 events. Events, and the hazard ratio crossed one so not significantly different, but they did show an increase in major hemorrhage. And this was 361 events versus 265 events. And that hazard ratio is 1.38 meaning that a person taking aspirin versus placebo was 1.38 times more likely to experience a major bleeding event versus a placebo patient. Speaker 1 15:22 And think about it, these are we're talking about older patients. So the risk of bleeding, if you compare it to younger, healthy individual, will be a slightly higher baseline risk. Anyways, an interesting finding came out of this trial: all‑cause mortality in the aspirin group was increased by 14%. This was not due to major hemorrhage or cardiovascular causes but was mainly driven by increased cancer deaths, particularly colorectal cancer. Dr. Sean Kane 15:54 And this was actually a really interesting finding, because previous literature almost supported the use of NSAIDs, specifically aspirin for the prevention of GI cancers. And this really didn't support that at all, which I found was really interesting. Speaker 1 16:07 Yeah, and again, you're looking at the patient population. This was healthy older patient population. So we can say that, maybe not so much for those patients, but we quite maybe don't know the evidence for younger patients and colorectal prevention. Dr. Sean Kane 16:21 So ASPREE basically said among elderly patients who were 65 to 70 plus years of age: fairly robust, large study, no difference in cardiovascular disease, increased risk of bleeding and maybe even a signal of some harm associated with GI cancers. Speaker 1 16:39 yep, and that's in a nutshell, the summary of the ASPREE trial. The second trial was ASCEND (A Study of Cardiovascular Events in Diabetes). It was a study of cardiovascular events in patients with diabetes focused on primary prevention, and it enrolled N = 15,480 patients. These were patients who were older than 40 years old with diabetes but didn't have any previous cardiovascular disease. Median follow up was pretty long, 7.4 years, and the intervention was 100 mg enteric‑coated (EC) aspirin versus placebo. And what we found in this trial was the relative risk reduction was 12% when we look at non fatal, mi stroke, transient ischemic attacks, Tia or vascular death, and that was excluding the intracerebral hemorrhage. But if you look at all these events separately, there was no benefit for a specific cardiovascular event. And interestingly enough, if you look at that Kaplan Meier curve, the benefit was only seen for the first five years. It was kind of lost thereafter, while the trial lasted for 7.4 years. Dr. Sean Kane 17:48 So of course, we're that's great that we've benefited basically cardiovascular problems by 12% certainly there must be a trade off to that, right? Speaker 1 17:57 There is, there is. So then this one looked at bleeds, right? So there were major bleeds, defined as GI bleeds, cerebral hemorrhage, or bleeds that would threaten the eyesight. And this was 29% higher in patients who were taking aspirin versus those who were taking placebo. And if you put that in perspective, consider the number needed to treat versus the number needed to harm. This was 91 patients needed to be treated to prevent one serious vascular event, while the number needed to harm was 112 to cause one major bleed. So we have this trial results. But what does the ADA 2019 set? Well, looking at the results of the ASCEND trial, ADA 2019 loosened their recommendation. It was always a level C recommendation previously as well, but this one was kind of just broadened up. They said it's still level C recommendation for those who have diabetes and increased cardiovascular risk after a discussion on their benefit versus risk of bleeding. So they are basically now turfing this to an individual clinician and asking them to look at the patient holistically and divvy up the risk versus benefit and assign aspirin therapy accordingly. Dr. Sean Kane 19:12 And I mean, hopefully this would be part of a shared decision making discussion with the patient, right? So if you have an older alcoholic patient who takes a lot of ibuprofen, maybe you should not give them aspirin. But if you have someone who's younger that has really high risk of cardiovascular disease in the next five to 10 years and a low bleeding risk, maybe you would be more apt to give them aspirin. This is more of a patient specific thing, versus a blanket recommendation. Speaker 1 19:37 Then Absolutely, yep, yep. So gotta have that when I'm on discussion for sure. Dr. Sean Kane 19:42 So then there's a third trial, the arrive trial. This is aspirin to reduce risk of initial vascular events. So this was about 12,000 patients. Included men about 55 years of age with two to four risk factors, or women more than 60 years of age with three or more risk factors. The 10 year risk was around eight to 9% so this would be classified as a low to intermediate risk population. Similar to the other two trials, they gave 100 milligrams of aspirin versus placebo. Followed them for five years because we already had a study of patients with diabetes. We excluded diabetics, we excluded those with a history of GI bleeding, concurrent anti platelets, anticoagulants and frequent NSAID use, which is consistent with the other exclusion criteria we talked about. And because only 61% of the patients were adherent, this led to a per protocol analysis, meaning that they only kind of investigated those that stayed on therapy and kind of did what they're supposed to within the trial. Yep. Speaker 1 20:37 And adherence rate for the other trial is out there, and it's at par with this trial too. But this study investigators kind of decided to look at the protocol analysis, and what they found was that aspirin did not decrease the combined outcome, and that was the cardiovascular outcome of first mi stroke, cardiovascular death, unstable angina or TIA, but the bleeding events, especially the GI bleeding events, were more than twice as likely in patients taking aspirin versus them taking placebo. So that was one analysis, and they because of the per protocol analysis, they were able to find some benefit, fatal and non fatal mi by 47% but again, this is not an intend to treat analysis. Dr. Sean Kane 21:22 So what was kind of the overall take home point, given that they had different analyzes and a fairly significant risk of taking aspirin, right? Speaker 1 21:29 And so this is the overall conclusion of the three trials: aspirin provides no additional benefit for primary prevention in patients ≥70 years old, or in non‑diabetic patients whose 10‑year ASCVD risk is <20% — particularly those with higher bleeding risk. So again, if you break it down, there's no evidence for older patients; diabetic patients may have some benefit. However, non‑diabetic patients with primary ASCVD risk <20% have uncertain benefit, and we must evaluate bleeding risk. They defined high ASCVD risk as >20%. So again, for the listeners, if you come across the statement high ASCVD risk, most of these trials defined that as >20% risk, calculated by the pooled‑cohort equation of the AHA/ACC 2013 guidelines. So what Dr. Sean Kane 22:39 I love to look for when there's a bunch of kind of muddy trials where they have different conclusions, is great review and meta analysis. And it sounded like you mentioned at the beginning of the episode that Jama recently published a systematic review and meta analysis, including these trials in addition to other trials that have historically been out there, right? Speaker 1 22:58 So they pulled pretty much all randomized control trials up until November of 2018 with at least 1000 participants who didn't have any cardiovascular disease and who were placed on aspirin versus placebo as the interventions. And so what this meta analysis looked at was 13 trials with 164 some 1000 patients and a patient or a participant follow up year of more than a million and they were looking at patients with the median age of 62 years. The range was 53 to 74 again, kind of meeting those requirements of other trials. We looked at 47% of the patients were men. They had good number of patients with diabetes, about 19% and that median baseline risk of cardiovascular event we were talking about, that 10 year risk, was about 9.2% at par with some of these trials. Dr. Sean Kane 23:55 The two main things that they looked at, which is what we've been talking about this whole episode, is cardiovascular risk prevention. So aspirin was associated with a decrease in the composite of cardiovascular outcomes. The hazard ratio was point eight, nine. So an 11% reduction, the absolute risk reduction was 0.38% meaning that if your tenure risk was 10% this brought you down to 9.6% the number needed to treat there was 265 Yep. Speaker 1 24:24 And if you look at the flip side, we're looking at major bleeding events. Aspirin was also associated with the increased risk of major bleeding compared to no aspirin. This hazard ratio was 1.43 and the absolute risk increase was 0.47%. The number needed to harm was 210 versus a number needed to treat of 265 — so the number needed to harm is smaller than the number needed to treat in that pooled population. Dr. Sean Kane 25:02 So basically, as a general rule of thumb, that means that you're more likely to cause harm giving aspirin for primary prevention, although you should recognize that number needed to treat and number needed to harm are sensitive to the baseline risk. So if someone has a really, really low risk of bleeding and a really high risk of cardiovascular events, they probably will benefit from it. The converse is also true. If they have a fairly low 10 year risk, let's say less than 10% but they're older, with risk factors for bleeding, then they probably will be even more likely to have harm than the number you did a harm of 210, Speaker 1 25:36 yes, absolutely. And that's why the meta analysis was laying out the foundation that the baseline risk was about 9.2% Dr. Sean Kane 25:43 really critical to understand that absolutely Speaker 1 25:46 so following those three randomized control trials and the JAMA meta-analysis and systematic review, we have the updates and recommendations from AHA/ACC, and this is what brought forward the news. And so breaking down, what are those recommendation it's a level, a recommendation for using low dose aspirin for primary prevention in adults 40 to 70 years of age with higher, again, higher a CVD risk. This higher risk is greater than 20% 10 year risk for patients who don't have diabetes, but greater than 10% risk for patients with diabetes who are not at increased risk of bleeding. Dr. Sean Kane 26:35 So then it's a level B recommendation that you should not recommend low dose aspirin routinely for primary prevention in very elderly adults, anyone above 70 years of age, and they recognize that if someone is 69 years old and they're on aspirin, then they have their birthday, they turn 70, it's not really clear what to do for them. My personal bias would be, if it's not broke, don't fix it kind of problem. So if they've been tolerating therapy for many, many years, why take that away? Clearly, they have a lower bleeding risk than other people who are on aspirin for a couple weeks then experience a GI bleed, right? Speaker 1 27:08 And I mean, you may have to evaluate, you're going to see this patients at least once a year, I'm hoping, but Medicare physicals and stuff. But you have to time and time again, evaluate their risk of bleeding, which it's a reality that none of these trials or even the guidelines talk about how to evaluate the bleeding risk, and that's where we're going to talk about the level C, limited data evidence is don't use aspirin for primary prevention in those with increased bleed risk. The drawback here, when it comes to bleeding risk is that we don't have a tool that these trials use to assess patients bleeding risk. They kind of came up with their own assessment on how to define bleed risk. And so right now, what we are working with when we are assigning patients bleed risk is just a list of things such as history of previous GI bleed or peptic ulcer disease or bleeding from the other sides, you know, looking at patients age greater than 70 having a history of thrombocytopenia, coagulopathy, chronic kidney disease, they're using medications that can increase risk of bleeding, such as the NSAIDs or the anticoagulants and the steroids. So that's where we are at. Dr. Sean Kane 28:18 And I would even add to that list, alcoholism. I see a ton of alcoholics that both have peptic ulcer disease or gastritis caused by alcohol abuse, but also fall risk. So typically, in patients that get drunk a lot, they also fall a lot because of imbalances. That's also another huge risk factor in my mind from the patients that I see. Speaker 1 28:37 Yeah, and the organization really understands that we don't have the right means to calculate the bleeding risk and we should be looking at patient individually. Dr. Sean Kane 28:46 So why don't we go back to our patient case, our 65‑year‑old gentleman, who is currently on aspirin and warfarin, he's never had a cardiovascular event in the past, although he does have plenty of risk factors for bleeding — specifically a hospitalization for a GI bleed five months ago — and he's concurrently on warfarin. So he actually would have been excluded from the trials we talked about because of his Warfarin use, right? Speaker 1 29:10 So he's still within that recommended age range, right? He's not above 70. Otherwise it would have been easy to say maybe not. But he doesn't have a personal history of ASCVD; his overall ASCVD risk seems to be low, but his bleeding risk is high. He just had an event. He's on warfarin, so that's an anticoagulant that increases the risk. So yeah, we could say right now that he's okay to stop taking the aspirin, but if he was a patient who had an MI in the past, obviously we would be looking at secondary prevention, and at that point aspirin would continue. Dr. Sean Kane 29:47 So Dr. Patel, if you were to discontinue aspirin on this patient, is there any need to do any tapering or any other strategy, or do you just stop cold turkey? Speaker 1 29:56 No. Cold Turkey. Stopping is completely fine. We can go ahead. And have him just say, take your last dose today. If you've taken it, don't worry about taking the evening dose. If you have no yet to be taken it, they can stop it right. Then there's no need to taper. Dr. Sean Kane 30:08 No, at least in my experience. And keeping in mind, I don't work in primary care, I work in intensive care, so typically, we try to not change chronic medications for patients unless it's the reason they came to the hospital, like a new bleeding event. But I know anecdotally, it's hard to stop medications. It's really easy to start new medications. So in my head, I'm envisioning a pharmacist making the recommendation, hey, let's get rid of that aspirin. And a number of questions coming up like, well, it's just a low dose. Isn't that? Speaker 1 30:36 Okay? Well, now we have the evidence right. Most of these trials we talked about used low dose aspirin, and we saw that the bleeding risk was significantly higher. And so even though low dose aspirin can cause bleeding again, that low is probably a misleading adjective. Dr. Sean Kane 30:55 And what about the buffered aspirin, or the enteric‑coated aspirin? Certainly that is thought to mitigate some of that risk, because the coating delays dissolution in the stomach — but it does not prevent the bleeding risk related to aspirin's pharmacology. Speaker 1 31:09 That's what you think, right? And that EC or buffered aspirin is basically a misnomer. Has nothing though, the way GI bleeding with aspirin occurred has nothing to do with the the buffered or the enteric coated property has to do with the pharmacologic property of aspirin, as you explained earlier, the thromboxane inhibition happens, and therefore the protective mechanism of the GI mucosa is compromised, and that's where the bleeding comes from. And I Dr. Sean Kane 31:37 think that as part of that discussion with that provider, in terms of them being worried about taking away something that decreases cardiovascular risk, that's a great time to talk about other strategies that do work, that don't put that patient at harm in terms of reducing that patient's overall risk of future cardiovascular events, right? Speaker 1 31:56 And we talked about how these three randomized control trials had patients with statin on there. So we're talking about other strategies. We know that these patients were on statin, but there were no subgroup analysis to look at whether statin conferred any different benefit or added to the benefit that aspirin provided. So there was actually another study in process that looking at aspirin and some of statin use, hopefully we'll get some more enlightenment, but the provider can talk to the patient about other preventative strategies, such as add a statin if they're appropriate, including lifestyle changes — diet, exercise, smoking cessation, better blood pressure control, and better blood glucose control — which can help lower overall cardiovascular risk, Dr. Sean Kane 32:41 and then, you know, we've already mentioned it a number of times, but I just want to re emphasize that we're only talking about primary prevention here. As a student, I frequently got these two topics confused and kind of brushed them under the rug and put them in the same group. But it really is critically important to say that we're only talking about patients that have never had a cardiovascular event. That's what we're talking about. This does not apply to someone who's had a heart attack or stroke or other ASCVD event who is likely indicated for aspirin, right? Speaker 1 33:09 And that's a whole nother Podcast Episode One, two and three to talk about. But yes, we are here only talking about somebody who never had a cardiovascular event, although they could have risk factors for having those cardiovascular events in future. So in kind of just summarizing what we discussed today, we know that the previous evidence for aspirin use and primary prevention has been kind of all over the place. We talked about how the guidelines were all over the place, but now with the new randomized, controlled trials in 2018 we have more light on the area, and we know that the benefit of adding aspirin in primary prevention does not outweigh the risk in most newly available evidence, Dr. Sean Kane 33:49 and based on the newest data, that we do have routine use of low dose aspirin for primary prevention in elderly patients about 70 years of age is not recommended, and it's also not recommended in those who have a higher bleeding risk because of this balance between bleeding risk potentially outweighing the cardiovascular benefit the patient may derive. Speaker 1 34:08 So who is it really recommended for? Use should be reserved for those aged 40–70 who have high ASCVD risk, including those with diabetes. We're looking at an ASCVD risk >20% for non‑diabetic patients and >10% for patients with diabetes. Dr. Sean Kane 34:28 And I love the fact that now we're really moving forward to a discussion with the patient about their risks and benefits of drug therapy and a potential for excellent opportunity for shared decision making. So again, an individualized approach is probably the answer here, right in terms of risk factors for bleeding, risk factors for future cardiovascular events, and kind of taking that into context of whether a patient should be started or discontinued from aspirin, absolutely. Speaker 1 34:55 Again, we're talking about primary prevention. So this is not even encompassed. Saying any of the patients who have had an event and need to be on a vital medication like aspirin, Dr. Sean Kane 35:05 well, again, we have all of the references available at our website, HelixTalk.com this is episode 97 and then finally, we love the five star reviews in iTunes. We love hearing from listeners about what they want to hear more of. So if you have an episode that you really think would go well with the podcast, email us. Our contact information is on the website. We'd love to hear from you. So with that, I'm Dr. Kane and I'm Dr Unknown Speaker 35:26 Patel, and with that, steady hard Narrator - Dr. Abel 35:30 if you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 35:41 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.