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 188 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is the clot thickens, key updates from the 2025 acute coronary syndromes guidelines. So, Dr. Patel, today we're talking about guidelines that are fresh off the press, that it's been a minute since these have been updated. So kind of exciting to talk about. What's new in ACs? Dr. Khyati Patel 00:52 Yeah, I believe the last update was in 2013 and so it's, what, 12 years since then, we haven't seen much of the updates. So I'm excited to talk about it's freshly, freshly published. Dr. Sean Kane 01:05 What's kind of important here is that this is a consolidated update of a couple different guidelines that have come out over the years. So our STEMI and NSTEMI guidelines and the 2015 PCI interventions for STEMI guidelines, and then dual anti platelet therapy guidelines, which, you know, were released in different years, and things like that. This is designed to kind of consolidate all of those, plus have new updates as well. Dr. Khyati Patel 01:24 And usually guidelines can be pretty long read. These are comparatively just 92 pages. And I, like you know that we handbook kind of like the most important pharmacotherapy related aspect, but it has comprehensive management of ACS guidelines and approach Dr. Sean Kane 01:41 and of course, like we in our show notes for again, Episode 188 at HelixTalk.com we have references to the 92 page guideline. So why don't we start with one big important section, which is the use of analgesics for chest pain. So when patients have an acute coronary syndrome event and STEMI or NSTEMI or unstable angina, they have chest pain, and the guidelines did touch on, how should we treat that chest pain? Dr. Khyati Patel 02:07 Dr. Kane, I remember opening up nitrate bottles and perhaps giving a dose of morphine. So are nitrates and opioids still the one recommended for the symptomatic pain control? Dr. Sean Kane 02:17 Yeah, those are definitely still the go to therapies. And the guidelines are really clear that nitrates or morphine, no matter what you're using, it's like a band aid, right? So this is for symptomatic temporary relief that probably does not improve overall clinical outcomes. So it's not like giving a nitrate is a mortality benefiting therapy in ACS patients, but we do it because it makes the patient feel better, so symptomatic relief, and potentially there's some benefit of as the patient calms down because their chest pain is better, that seems like a good idea. It's just that we don't have a firm trial out there that has demonstrated a clinical benefit of doing that, Dr. Khyati Patel 02:53 and you're saying for long term management, they probably need interventions such as like revascularization, using a stent or a bypass, or so Exactly. Dr. Sean Kane 03:02 So if you think about it, like if a patient had a completely clogged coronary artery, if they responded to nitroglycerin and they felt a little bit better, that's good, but you still haven't fixed the problem, which is a clogged coronary artery, right? So this is a temporizing measure to help with the pain, Dr. Khyati Patel 03:17 yeah, and as to remind the audience, you know, there are some criterias for when we can use nitrates, right? Like drug interactions come to mind, or obviously they lower the blood pressure. So certain those parameters are also explained in the guidelines Exactly. Dr. Sean Kane 03:31 So the guidelines say you need to have a systolic blood pressure of at least 90, which is kind of low if you think about it, because that systolic pressure in general will go down when you give a nitrate. And then they also comment that if you have someone, based on EKG findings, that might have a suspected right ventricular infarction, which is a pattern on the 12 lead EKG, that they are more prone to having more severe hypotension. We call those patients preload dependent, where, if you reduce the venous return to the heart, that the right ventricle may not work as well, so you might avoid a nitrate in those patients. Yeah. Dr. Khyati Patel 04:04 And the drug interaction, I still remember being more like, the question is those PDE-5 inhibitors; we cannot combine them if a patient has taken one recently, because, again, it results in a greatly lower blood pressure. Yeah. Dr. Sean Kane 04:17 And that duration of time that you have to wait differs, so like Viagra or sildenafil, 24 hours, Cialis or Tadalafil, the Weekender, it's 48 hours. So it kind of depends on which PD five inhibitor you're talking Dr. Khyati Patel 04:29 about, yeah. And so patient history is very important to collect here. Dr. Sean Kane 04:32 And then there's different ways that we can give it. The main one is a sublingual tablet that you put under your tongue so you don't swallow it. The typical dose is 0.3‑0.4 mg comes in two primary strengths, and then you can use it up to every five minutes as needed for chest pain, but the maximum is three doses. Dr. Khyati Patel 04:50 And with the sublingual you know how fast it gets absorbed and starts to work, you wouldn't think you'd need additional routes, but I guess the IV infusion route is available. Dr. Sean Kane 05:00 Definitely, and we use this all the time in the ED and ICU setting, and this is for someone who more or less needs a bigger nitrate dose and their blood pressure can tolerate it, and they're not getting super nauseous or hypotensive from the nitrate that we give sublingually. And the main thing with the IV infusion is that we're going to titrate that infusion to way bigger doses than what you could get sublingually. And because it's an infusion, it doesn't kind of start and then wear off quickly, because we're giving it continuously. The downside, though, is it does drop your blood pressure a lot more than a sublingual will, and patients develop tolerance or tachyphylaxis to it over time, so after about a day, it probably isn't doing very much anymore. That's actually a very common clinical thing that happens in clinical practice is patients will be getting IV nitrate or even topical nitroglycerin for 2–3, 4–5 days, but after about a day, the effects really do wear off quite Dr. Khyati Patel 05:53 quickly, and if they still have that continued pain, what is the option then? So that's where our Dr. Sean Kane 05:58 opioids come in, and we think about like MONA, whatever for our acronym, and the M is for morphine. And this is actually way more controversial than you might think. Dr. Patel, if someone has chest pain and you give them a nitrate and they still have chest pain, or they can't take a nitrate and they have chest pain, we do still recommend an opioid, but there's some downsides to doing that, right? Dr. Khyati Patel 06:21 I think the way I understand morphine works that it releases the histamine, and that kind of ends up opening the blood vessels, so causing vasodilation, and it's a good thing that kind of helps improve the blood flow and lowers that pain sensation. Dr. Sean Kane 06:35 But the downside is that when patients have an acute coronary syndrome event, you're at least going to give them aspirin. In some cases, you'll give them an oral P2Y12 inhibitor like clopidogrel or Plavix, and when you do that, opioids work on the MU opioid receptor to help with pain, but they also work on that same receptor in your GI tract that slows everything down – that opioid‑induced constipation is also opioid‑induced slowing down of peristalsis in your stomach, for example, which can delay you getting your P2Y12 inhibitor as an example, absorbed into your blood. And we do know that in patients that need to have an opioid, their outcomes are worse. And is it because the opioid is making it so the P2Y12 inhibitor doesn't get in your blood as quickly, or are those patients just having more severe anginal symptoms, and the morphine, or the whatever opioid we're giving doesn't actually hurt anything, we're just kind of selecting for a sicker patient population. Dr. Khyati Patel 07:29 And is that the reason this opioid therapy for pain control is more like a secondary option. You want to do nitroglycerin first, unless there is it's not working or it's contraindicated for some reason. Then you go with the other Dr. Sean Kane 07:42 option, exactly. And then the other option that is mentioned in the guidelines is fentanyl. So, you know, again, Mona or Moana, we always think of the M for morphine, but the guidelines do say that fentanyl is fine, as long as we acknowledge that you don't get the histamine release. Then, two, it's a synthetic opioid. So whether a patient has codeine or hydrocodone or morphine allergy, fentanyl is good to go. No problem there. But the downside is it has a really short half life, so patients need to be redosed with fentanyl every 30 to 60 minutes versus with morphine every two to four hours. Dr. Khyati Patel 08:13 Yeah. So I think just dosing demand and nursing demand may be high if you use one versus the other. Dr. Sean Kane 08:20 So that was one big section. The other big section, which I would say is something that many of us have seen coming a little bit, is the recommendations related to p2 by 12 inhibitors. So this is our clopidogrel, prasugrel and ticagrelor. Dr. Khyati Patel 08:33 And when we talk about these P2Y12 inhibitors, the guidelines reminds us that this is not just use up P2Y12. This is in addition to the standard aspirin therapy. So here we're talking about that dual antiplatelet therapy or DAP therapy. Dr. Sean Kane 08:48 Yep. And the thing that we've seen in Europe already, that now the American guidelines are in line with, is that for patients with NSTEMI or STEMI, who get PCI and PCI is percutaneous coronary intervention. This is a coronary stent placed in a coronary blood vessel for those patients that get PCI, the recommendation is prasugrel, brand name Effient or ticagrelor, brand name Brilinta as a preferred therapy over clopidogrel or Plavix. Historically, the recommendation was not as much in terms of preferred therapy. Now, the preferred therapy is prasugrel or ticagrelor if you're doing a PCI. Dr. Khyati Patel 09:23 And when it comes to NSTEMI or STEMI patients without PCI, the ticagrelor is going to be preferred over the clopidogrel, and we're going to reserve prasugrel only for the PCI patient. So again, this is without PCI category. It's not recommended here, Dr. Sean Kane 09:39 and it's not that the prasugrel is good or bad in non PCI patients, it just hasn't been studied. So because the prasugrel study was just in PCI, that's where that recommendation comes from. Dr. Khyati Patel 09:50 So some of the clinical pearls to kind of keep in mind of these P2Y12 inhibitors, as you mentioned, Dr. Kane, you know, for patients who are having PCI, clopidogrel is like the last option; you want to use the other two first, and that's because we know that it's least potent. It takes longer to get to that peak platelet inhibition. And we also know that there's quite a bit of variability between patients based on the pharmacogenomics, especially that CYP2C19 variability, Dr. Sean Kane 10:22 that's absolutely true, and despite the guidelines really not preferring clopidogrel, we're still going to see a lot of clopidogrel in clinical practice. And the reason for that is that it's still cheaper than the other two branded therapies. And the main reason that we're not preferring clopidogrel is that it doesn't work as well, but the benefit is that it has a lower incidence of bleeding compared to the other P2Y12 inhibitors. So potentially, if you're willing to accept a lower efficacy in exchange for a better bleeding profile, you might pick clopidogrel as well. So cost and bleeding are reasons why you might have a patient specific decision to deviate from the typical recommendation, from the guidelines. Dr. Khyati Patel 11:03 When it comes to prasugrel, you know, it is contraindicated in patients who have history of stroke or transient ischemic attacks, and when I when we are using it in older patients, like 75 years of age or older, or patients who are underweight, that is less than 60 kilograms, we may have to either use it with dose reduction or avoid it altogether. Dr. Sean Kane 11:26 And then for ticagrelor, kind of the fun fact that is mentioned specifically in the guidelines, because this definitely comes up, is about 10 to 15% of patients who are started on ticagrelor, brand name berlinta, will have subjective, transient dyspnea, which means that they will feel short of breath. Everything looks fine with them, except they have this transient dyspnea that gets better over time. We can also see some ventricular pauses, or even like a bradycardia type thing. What's really cool about ticagrelor is that we think that these two side effects are driven by its chemical similarity to adenosine, and adenosine is a therapy that we use for patients with really fast arrhythmias that can basically, like, control, alt, delete the heart, like it just stops everything for a minute, and then you go back into, hopefully, a normal sinus rhythm. And ticagrelor shares some chemical structural similarities with adenosine, and that might be why we see the side effect profile. The other thing to note is that it has a warning that you can't exceed maintenance aspirin dose of more than 100 milligrams per day. So these patients will still get their normal 324, 325, of loading dose aspirin. But on day two, you should drop that aspirin dose to the typical 81 milligram. You shouldn't maintain a 325, milligram if you're going to use Dr. Khyati Patel 12:42 Ticagrelor, that makes sense. And I think the other point of discussion that always comes about is, how long should we have these patients on that dual anti platelet therapy, right? So what is the discussion in the guidelines in terms of how long they should be used? Dr. Sean Kane 12:57 And this is an area that definitely, I think people were waiting on, because we've seen a bunch of different trials over the past decade where they've manipulated how long to have dual antiplatelet therapy for or discontinuing the aspirin component and continuing the P2Y12 component for different amounts of time. Dr. Khyati Patel 13:14 I will tell you that I was so confused anytime this question came up, I had to dive into the primary literature, because I was getting all confused. I mean, different literature that was out there. Dr. Sean Kane 13:24 So kudos to the guidelines for keeping it fairly simple. And the main takeaway, I would say, is maintaining the line, which we've always had. Most patients should maintain DAPT for 12 months. Dr. Khyati Patel 13:37 And that's as simple as that, continue to app for 12 months. Yeah. Well, I guess there are some alternatives to consider in patients who maybe are at higher risk, because, as we know, you know, using not one but two anti blue therapy does increase their risk of bleeding. So what are some of those options here? Dr. Sean Kane 13:52 So one thing that I thought was really neat is that they acknowledge that if a patient has a high GI bleed risk, that giving a PPI is a smart move, and that you should consider doing that. And when we covered NSAIDs for HelixTalk, we actually talked about this, that NSAIDs, we have a lot of data that giving a PPI on top of your NSA reduces your GI bleed and ulcer risk, and they're acknowledging that with this as well. So with dual antiplatelet therapy, high GI bleed risk, you can consider a PPI for those patients. Dr. Khyati Patel 14:20 I'm going to remind the audience about the de prescribing episode and say that once they're actually done with adapt therapy, please re evaluate the use of Dr. Sean Kane 14:28 continued ppi. Exactly. Yep. Dr. Khyati Patel 14:31 And then I believe the DAPT with the preferred P2Y12 inhibitor like ticagrelor or prasugrel for one month is an option to then switch either of these P2Y12 inhibitors to clopidogrel for the rest of the 11 months. And that kind of goes back to what you said, Dr. Kane, that maybe clopidogrel gives us a little bit of less bleeding risk. And that's the strategy here utilized. Dr. Sean Kane 14:54 And also, we know from clinical data that the time period of highest concern in terms of, say. Stent thrombosis or other coronary vascular events happening is probably within the first month, not at month like 11 after PCI. So I like this recommendation a lot, because it focuses on both minimizing cost to the patients. You have one month of the higher cost therapy, followed by 11 months of clopidogrel. And like you mentioned, the bleeding risk is probably more favorable where you have a more aggressive, higher bleed risk, but better efficacy therapy for one month and then you drop it down for the 11 months after. But again, most patients don't need to do this, and if they have insurance coverage and they can't afford it, I do want to just emphasize the guidelines say, for most patients, their preferred therapy is 12 months of a preferred P2Y12 inhibitor plus aspirin, yeah, Dr. Khyati Patel 15:43 and with again, controlling the bleed risk, the guidelines are also recommending in the high bleed risk, patients to do dap therapy for one month and then decide to just do monotherapy, either with the aspirin, the low dose aspirin, or a P2Y12 inhibitor. And I thought Dr. Sean Kane 15:59 this was interesting, because in my head, I would always say, why would you not just use aspirin monotherapy if you're going to do monotherapy? But there's actually kind of, not surprisingly, the drug companies have studied their P2Y12 inhibitor being the monotherapy after that first month. So for example, ticagrelor actually has the best data in terms of, it's been specifically studied where you do DAPT for a month, and then, instead of doing just aspirin, you do ticagrelor after that. And then that has been studied as monotherapy for roughly one to three months. But again, the recommendation is going to depend on your patient bleeding risk and things like that. Dr. Khyati Patel 16:37 And then is there a patient population, Dr. Kane, where we would consider going beyond 12 months for adapt therapy, yeah. Dr. Sean Kane 16:44 And this is where some of that, like confusing literature, has come from, where they extend it beyond the 12 month period. And the guidelines basically say it's a case by case decision. If you continue beyond 12 months, you're going to increase the patient's bleeding risk, but the benefit would be that you're going to reduce the risk of ischemic events in the future. So if you have someone who has a very low bleed risk but a very high risk of having a new coronary event, then they might qualify for prolonged adapt therapy. But they don't specifically say who that patient population is. So it's up to you as a clinician to kind of, on a case by case basis, make that determination. Dr. Khyati Patel 17:19 And then obviously we have some patients who might be on anticoagulation. Maybe they're taking it for afib, ACS or even VTE reasons, and so they're in that TOAT situation, which is triple oral antithrombotic therapy. So they have the adapt the dual antiplatelet therapy plus an anticoagulant. Maybe it's, you know, an apixaban, or maybe it's warfarin, Dr. Sean Kane 17:41 and obviously these patients have a very high bleeding risk, right? So the guidelines do comment on this, and kudos to them, because this is a super difficult patient population to manage. But they say, after PCI, do your TOAT therapy, triple oral antithrombotic therapy, and then they say, after about one to four weeks stop your aspirin, and that means that you're going to continue your p2 i 12 inhibitor and your oral anticoaguag, kind of indefinitely. But they do mention that if you're going to pick a p2 i 12 inhibitor, clopidogrel probably is better because of its lower bleeding risk, and if you're going to pick an oral anticoagulant, probably a doac over Warfarin is better, again, primarily because of the lower bleeding Dr. Khyati Patel 18:20 risk, and that makes sense with the chest guidelines for anticoagulation management in those patients. Dr. Sean Kane 18:26 So, so that's kind of our P2Y12 inhibitor showdown, or recommendations that we saw in the guidelines. The guidelines also did a really good job talking about parenteral anticoagulation in the setting of an ACS event, too. Dr. Khyati Patel 18:40 Oh yeah, don't we forget about that all the time? Dr. Sean Kane 18:43 Actually, we do. So it's very common that students when precept, and I'll ask, you know, what do you give to that patient who's having an ACS event right now? And usually they forget about the anticoagulant, but it's actually a really important therapy that's given in the setting of an acute Mia patient. Dr. Khyati Patel 18:59 And so those patients who are not going under an intervention like a PCI or CABG, usually will will go with heparin. So you do the loading dose and then the maintenance dose they're apt after, yeah, Dr. Sean Kane 19:09 and heparin is just kind of easy and especially in the short term. Usually you don't know for sure, for sure that they aren't going to PCI, because stuff can change. But if you definitely are going to medically manage that patient. Heparin is preferred, but the guidelines do say alternatives could be enoxaparin or Lovenox or phonoperinex or rickstra. Just acknowledging that heparin is the best if you have renal impairment, phonoperinox is the worst if you have renal impairment, there's a lot more precautions with that one. Dr. Khyati Patel 19:36 And then if they have the PCI or CABG plan prior to the procedure, we're going to use heparin again, short acting. You can turn off that knob, and then it reverses pretty quickly. But then there are some other interventions to do during the PCI and then thereafter as well. Dr. Sean Kane 19:53 And I think pharmacists, this is where a lot of the confusion comes from, especially like when student pharmacists are learning about anticoagulants. In the setting of acute coronary syndromes, basically you're going to use heparin before you do a procedure, and that's the easiest thing to remember during the procedure. Usually, pharmacists actually aren't that involved in that process, because they're in the cath lab and the cardiologist is the person choosing the anticoagulant. Oftentimes, they have strong preferences about what they want to use and things like that. But just for everyone's reference, during the PCI, your options are to continue heparin that you've already been on, or you can switch to bivalirudin. The brand name is Angiomax. This is a direct thrombin inhibitor. It's controversial, but there is some data that maybe you have lower mortality, maybe a lower bleeding risk if used by bivalirudin versus heparin. And a lot of the data is coming from STEMI versus NSTEMI population, but there is data out there. You could also choose to use enoxaparin during the PCI, but this has a lower kind of strength of recommendation. And then the guidelines are really clear that during PCI you do not use fondaparinux. And the reason is, in those trials, they saw more blood clots on the catheter tips during PCI. And I would say that, just in general, fondaparinux is not super common regardless, for 99% of patients with ACS events, anyway. But specifically, we would not use fondaparinux in the setting of PCI. Dr. Khyati Patel 21:16 So during the PCI, it's either continuing the heparin or switching it to bivalirudin, Exactly, yep. And then after PCI and CABG, we're going to go ahead and stop the anticoagulation. Once we know that revascularization is achieved, unless, obviously your patient was a prior candidate for having anticoagulation, then you will do that TOAT therapy, but other and then transition them to that appropriate anticoagulant. But otherwise, if there is no continued indication for anticoagulation, it can be stopped Exactly. Dr. Sean Kane 21:46 So I think to de‑confuse the situation, you can't go wrong with heparin. It's first line for everybody, no matter what. So if you aren't sure, go with heparin as an IV bolus followed by an IV infusion. Dr. Khyati Patel 22:00 The bivalirudin is going to be your option during the procedure itself, if you don't want to do heparin. Dr. Sean Kane 22:05 And you might see enoxaparin for non‑PCI patients. It's really uncommonly used in PCI patients, and fondaparinux is basically not used, but especially not used during PCI. Dr. Khyati Patel 22:17 Dr. Kane, that was interesting, because you're right. We don't, you know, we think about the p2 by 12 inhibitor therapy, but don't focus on that acute need of anticoagulation. So this was a good refresher. We're going to move the needle a little bit and go to the discussion along my alley the lipid management. Right? Those patients have ACS, which categorizes itself under the global umbrella of atherosclerotic cardiovascular disease. And patient's going to be getting a statin therapy. So what are some of the recommendations that the guidelines mentioned here, and how they're slightly different than our 2018 cholesterol management guidelines? Dr. Sean Kane 22:52 Yeah, I feel like Dr. Patel, we've made a bunch of changes over time, of like, what LDL target do we have? Who gets extra therapies? Kind of nice, but not surprising that it didn't change, is that everyone who's had an ACS event should get a high intensity, high dose statin that has been the way for a long time. So that means an atorvastatin, or Lipitor, 40 or 80 milligrams a day, or rosuvastatin, Crestor 20 or 40 milligrams a day. That hasn't changed, and we're looking for roughly an LDL reduction for those patients of about 50% and in clinical trials, by taking that statin, it reduces their future risk of an ASCVD event by about 30% which is actually our biggest reduction of all the therapies we're going to talk about. Dr. Khyati Patel 23:31 Yeah, and these guidelines are also talking about what to do if your patient was started on that high intensity statin but did not achieve below 70 milligram per deciliter, I'm going to say it LDL goal. So they're kind of going after not sort of a goal to achieve, but when to start thinking about adding a non statin therapy that could help lower the LDL further. And so the guidelines are recommending that we could use these additional LDL lowering agent if their LDL is staying above 70 despite the use of high intensity statin. And interestingly enough, they're saying possibly you can even do that for patients who are between the LDL of 55 to 69 This is not the strongest recommendation, but it is a new recommendation with some low level of evidence behind it. So I'm definitely surprised by this recommendation Dr. Kane, but we're hoping with some of the other non statin agents, like PCSK9 inhibitors, providing such robust LDL reduction, that we might be able to get there. Dr. Sean Kane 24:37 And really like again, we've seen a pendulum swing back and forth of LDL goal, or no LDL goal, and then you want a 50% reduction, or do you want it less than 70? So today, as of the 2025 guidelines, just to reiterate, the new guidelines say you should be adding more stuff after your statin if your LDL is not less than 70, and if you're between 55 and 69 maybe you still think about adding more stuff. So really the only time you might not add extra stuff is if their LDL is less than 55 but again, this is like a lower quality of evidence or recommendation in terms of that second category of that 55 to 69 patient population. Dr. Khyati Patel 25:18 overall, talking about these goals and stat, you know, high intensity statin, then using the non‑statin, what really this means is bottom line, ACS patients are going to get your high intensity statin, regardless of the LDL. You could consider addition of ezetimibe. We know that there is a study based on the IMPROVE‑IT trial results showed benefit in patients who were in the settings of ACS‑related hospitalization, so that definitely is a possibility. But we can also use other non‑statin agents such as PCSK9 inhibitors or bempedoic acid, which does have ASCVD risk reduction data. Dr. Sean Kane 25:52 And then the other change is that they're suggesting to recheck a lipid panel in four to eight weeks. The classic teaching has always been four to 12 weeks. You definitely have to wait at least a month to see the effects. And I'm guessing that they chose a shorter time window, so that you are adding your additional non statin therapy earlier on, up to a month earlier, if you check it a little bit sooner. Yeah. Dr. Khyati Patel 26:15 So again, the bottom line here is, if their LDL is above 70, go ahead and add that non‑statin. If it's between 55 to 69 you can quote, unquote, consider a non‑statin addition. And then if it's less than 55 that you don't need to add that. Dr. Sean Kane 26:31 Then in terms of that non‑statin therapy, we already talked about ezetimibe (Zetia), and this is the one that you could potentially add during the index event of ACS. So regardless of what their LDL is, you just give them statin plus ezetimibe, and then check in one to two months, if you haven't done that at that check, if you're not at your LDL goal, you could consider adding ezetimibe. This is the cheapest one. It's an oral tablet, not an injection, and it lowers your LDL by about 20%; the kind of downside is that it doesn't have a fantastic ASCVD reduction in the clinical trial that this examined, and basically like fresh post‑ACS patients, it reduced their future risk by 6% which is really not that much, but it's something. And we need to be aware that ezetimibe can increase your LFTs and cause myopathies, which statins do as well. So we should be aware of that side effect profile, Dr. Khyati Patel 27:22 and the other agent we discussed was PCSK9 inhibitors. These are monoclonal antibodies, and they are given via sub‑Q injection. So they're still brand name, they're still injection therapy, some of those caveats to keep in mind, but they do provide that excellent LDL reduction that we were talking about earlier, up to 60% and lowers the ASCVD risk by about 15%; side‑effect wise, you know, these are fairly nicely tolerated therapies, but injection site reactions have been seen as well as hypersensitivity reactions, and the two PCSK9 inhibitors that are in the market are Repatha, generic name is evolocumab, and the other one is Praluent. The generic name is alirocumab. Dr. Sean Kane 28:05 And then another option that we have, which is a little bit newer to the market, is called bempedoic acid. Brand name is Nexletol. This is also an oral tablet like Zetia, and it's also in combination with ezetimibe called Nexlizet. So it has the benefit of an oral tablet, but the downside that it is a brand product that is going to be more expensive than ezetimibe. Just like ezetimibe, we're seeing an LDL reduction of roughly 20% but in clinical studies, it did reduce ASCVD risk by 13% which is still kind of a mediocre improvement, but we have to note that that was only in statin‑intolerant patients, so we actually don't know what the ASCVD reduction would be if you added this to a statin, as opposed to just that statin‑intolerant patient population. And then, in terms of risks, kind of interesting, it does increase your uric acid level in your blood. So if a patient has gout, they're at a higher risk of a gout attack. Or if they don't have gout, they could have their first gout attack with this. We can see gallstones, LFT abnormalities. And then another interesting one is tendon rupture, which is rare but serious, something to know about that medication. Dr. Khyati Patel 29:09 And then, last but not least, we have inclisiran as a generic name. These belong to small interfering RNA against PCSK9 mRNA. So technically you can say it's almost inhibiting that PCSK9 protein, so it is, again, sub‑Q. So you're looking at those injection site reactions; in clinical trials, we noted LDL reduction of up to 50% but we unfortunately don't have the ASCVD risk reduction data just yet, and I think the side effect profile might be too premature for us to say that they're completely safe. Dr. Sean Kane 29:45 And then the guidelines also comment about statin intolerance and Dr. Patel, I believe there's even statin intolerance guidelines out there to talk about what to do, but in short what they talk about in the guidelines is one verify that they're actually intolerant. So that means to be statin intolerant, you have to try two different statins, and at least once, try the lowest FDA approved dosage form of that statin. And if you can't tolerate the lowest dosage of one statin, and you've tried a different statin, now we call you statin‑intolerant. Dr. Khyati Patel 30:17 Yeah, and I think this process is not as focused on or delineated properly. It's very easy for us to see that one statin and patient's intolerance or allergy list, and then assume that patient is across the board statin intolerant, and usually that's not the case. So intolerance to one statin doesn't mean that they're intolerant to another. We also need to evaluate some drug interaction that can also increase the statin levels and put patient at a higher risk for myopathies and stuff. And if those interacting drugs are, sorry to say, not as important as statins are, then we should probably prioritize statin therapy and think about adjusting those other interacting drug therapies. Dr. Sean Kane 30:56 And I just want to highlight again that statins are our best ASCVD‑reducing therapy, of all of our therapies by a 30% reduction. So it's actually really big deal to not be able to give a post to my patient a statin because of an intolerance that hasn't been fully investigated. Then, of course, if we truly say yes, there's statin intolerant, that's where we reach for all of our non statin therapies that we just talked about. And you know, we have a lot of options here, acknowledging that probably just zedia, for example, is not going to cut it. If their LDL is really high, you probably need to reach for something like a PCSK9 inhibitor if their LDL is high enough for Dr. Khyati Patel 31:32 that, yeah, because you got to pay attention to those LDL reductions there. Dr. Kane, the guidelines kind of were very comprehensive, looking at all pharmacotherapies. So they also kind of reiterated the use of beta blockers. As soon as the patient is stable, go ahead and make sure we are adding the beta blocker therapy. So that's not a change. However, there was one study results that they did not include in the guideline. Dr. Sean Kane 31:56 Yeah, so kind of hot off the press two now a year removed, was the reduced AMI trial, and this was a trial that looked at post mi patients who had a normal ejection fraction. So we already know that if you have a low ejection fraction, you should get a beta blocker, and only specific ones for that reduced EF patient population. And historically, we've always added beta blockers to everyone who's had an MI. And the recommendation has been try to add an oral beta blocker within 24 hours, but the reduced AMI trial looked at, maybe we don't need to. So in that reduced AMI trial among patients that had normal ejection fraction, the use of a beta blocker did not reduce mortality or recurrent mi compared to no beta blocker. So it does kind of call into question, how important is that beta blocker therapy, Dr. Khyati Patel 32:41 and then the guideline is also going over. Kind of the RAS agents are aces and ARBs. They're saying if a patient has high risk ACS, so again, your patients with low ejection fraction ≤40% they have other risk factors, like hypertension, diabetes, or they have had an anterior STEMI, then either ACE or ARB is okay to go with. Dr. Sean Kane 33:03 And then, of course, for those with a reduced ejection fraction heart failure, ACS with or without diabetes. So you know some trials specifically looked at diabetes as basically equivalent as if you had a heart failure symptom, we should be thinking about an MRA for those patients, so a mineralocorticoid receptor antagonist; the typical one is going to be spironolactone. We also have eplerenone, and then a new one, finerenone. So we have a couple options in this category. Dr. Khyati Patel 33:30 as well. And if you have a patient who is not high risk ACS patient, then again, you could use ACE inhibitors or ARBs. However, recommendation over here is a little bit lower quality recommendation. Dr. Sean Kane 33:42 So Dr. Patel, to kind of wrap up today's episode. One big take home point that I think is really important to talk about is nitrates are the first line for chest pain, followed by opioids after that. But it's only for symptoms, and some patients may not be appropriate for nitrates. So drug interactions, hypotension, things like that, and then opioids have a theoretical problem of delaying the absorption of certain medications, like your P2Y12 inhibitor, so we try to not give it unless we really need to. Dr. Khyati Patel 34:10 And then another thing to solidify in terms of P2Y12 inhibitors is that prasugrel and ticagrelor are preferred over clopidogrel in most of these patients. However, you are going to look at your patient specific factors, including whether they're going under PCI or not. That will let you pick the appropriate P2Y12 Dr. Sean Kane 34:31 inhibitor and then commonly missed by students in the setting of ACS, we should anticoagulate All patients unless there's like, a clear contraindication, which would be really unusual. Heparin is good for everybody. So heparin is very commonly used for that. There are some alternative anticoagulants besides heparin, based on if you're going to go to PCI or CABG or not. And during PCI or CABG, the main alternative is going to be bivalirudin during the procedure itself. But you're still going to start with heparin before they get. The cath lab, Dr. Khyati Patel 35:01 and sort of like looking at the lipid management category, the LDL goals after having ACs have changed here, according to this guideline, and patients who have ACS should achieve LDL reduction of less than 70 with the consideration of even lower LDL of 55 to 69 and at that point, if the patient's not meeting these goals, you could consider non statin therapies in addition to that high intensity statin that was started on a patient. Dr. Sean Kane 35:32 So Dr. Joe, for the audience, I would encourage them to take a look at the guidelines, because they are very comprehensive and way more content than what we covered today. So we have a link in our show notes at HelixTalk.com to those new 2025 guidelines. Again, this is episode 188 we also have a mailing list at HelixTalk.com where you can get emails when new episodes come out. And we love the five star reviews and iTunes or Apple podcasts or wherever you're listening to us. So keep those coming. So with that, I'm Dr. Kane Dr. Khyati Patel 35:59 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 36:03 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 - ? 36:14 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.