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Show Notes

Pearl 1: Indications

    • Antithrombotic therapy overview
      • Antiplatelets (COX1 inhibitor, P2Y12 inhibitor)
        • Use in high-velocity flow states
          • Myocardial Infarction, Cerebrovascular Accident, Peripheral Arterial Disease, etc. 
      • Anticoagulants
        • Use in low-velocity flow states
          • Deep Vein Thrombosis, Pulmonary Embolism, stroke prophylaxis in Atrial Fibrillation, etc.
        • Mechanical heart valves
          • Use Warfarin (Vitamin K antagonist) 
    • DAPT indications
      • Post-ACS event
        • All of these patients should be thought of as a more thrombotic phenotype
        • Therefore, we favor 12 months of DAPT regardless of whether a stent was placed or not
        • CURE Trial in 2001 compared Aspirin monotherapy to Aspirin + Clopidogrel for 3-12 months after PCI with a mean duration of 9 months
          • Absolute risk reduction of 2.1% for primary composite outcome of cardiovascular death, nonfatal MI, and stroke 
          • Increased absolute risk of major bleeding by 1%,  but did not increase life threatening bleeding  
      • Stable Ischemic heart disease (SIHD)
        • In other words, non-ACS setting
        • Can think of these patients as a less thrombotic phenotype
        • Consider DAPT if a stent is placed to achieve two primary goals: 
          • Short term goal 
            • Reduce risk of stent thrombosis 
            • Life threatening event which occurs while stent is in process of endothelialization 
            • Classification and criteria for stent thrombosis 
            • Important note: Does NOT mitigate risk of in-stent restenosis (which is a more chronic process due to endothelial overgrowth and is not influenced by DAPT)
          • Long term goal
            • Reduce risk of de novo ischemic events
    • Severe diffuse atherosclerosis
      • In addition to CAD, antiplatelet agents also have benefit in PAD and cerebrovascular disease 
      •  Phenotypically high-risk group
        • May see DAPT in these patients, especially if comorbid CAD

Pearl 2:  Medications 

  • Aspirin → works as a COX-1 inhibitor
    • Not reversible
    • Contraindications include active bleeding, hypersensitivity, severe hepatic failure 
  • Options for P2Y12 inhibition: 
    • Clopidogrel (Plavix) 
      • Prodrug, variable hepatic metabolism
      • No reversible agent
    • Prasugrel (Effient) 
      • Prodrug, predictable hepatic metabolism
      • No reversible agent
    • Ticagrelor (Brillinta) 
  • Consider three factors: 
    • Potency
      • Prasugrel most potent, followed by ticagrelor, then clopidogrel
      • In the ACS setting, we tend to prefer more potent agents like ticagrelor or prasugrel in the absence of contraindications
    • Bleeding risk
      • Increased bleeding risk is always the trade off of increased potency 
      • We avoid prasugrel in patients age > 75, history of TIA/stroke, and hepatic dysfunction
      • Also avoid ticagrelor in patients with history of ICH
    • Feasibility
      • Side effects
        • Ticagrelor inhibits adenosine reuptake, which can cause bradycardia and dyspnea, sometimes resulting in patient self-discontinuation
      • Dosing frequency
        • Clopidogrel and prasugrel are once per day, while ticagrelor is twice per day 
      • Price (according to GoodRx in Mar 2020 in USA)
        • Clopidogrel generally affordable (~$15)
        • Ticagrelor is costly (~$300)
        • Prasugrel is now available in a generic version, making it affordable  (~$10-$15)
  • Show me the data:
    • TRITON-TIMI 38 trial demonstrated prasugrel compared to clopidogrel reduced rate of ST (2.4% vs 1.1% at 6-15 mos of treatment)
      • Increased risk of major bleeding, including fatal bleeding
    • PLATO trial demonstrated ticagrelor superior to clopidogrel in reducing composite death from MI/stroke/vascular causes (11.7% vs 9.8%), as well as lower rates of stent thrombosis 
      • Ticagrelor group did have increase in non-procedure related bleeding (including ICH)
    • ISAR-REACT 5
      • In ACS populations, prasugrel reduced rates of death (4.5% vs 3.7%), MI (4.8% vs 3.0%), and stroke (1.1% vs 1.0%) compared to ticagrelor at one year
      • However, there was a trend toward increase in major bleeding in the prasugrel group (5.4% vs 4.8%, p = 0.46)
    • Bottom line:
      • Ticagrelor and prasugrel are both slightly superior to clopidogrel (2-3% absolute reduction over 1-3 years) with regard to ischemic endpoints, but come with a slightly elevated bleeding risk (1-3% absolute increase) 
  • Transitioning P2Y12-inhibitors:
    • Must remember to RELOAD patients when switching between agents
    • For more details, click here 

Pearl 3: Duration: How long do you keep patients on DAPT? 

  • Optimal DAPT duration (current guidelines but is a moving target given new data below)
    • Following ACS event (stent or not): 12 months
    • Following stent placed in non-ACS setting: 6 months
  • Shorter duration 
    • Possible primarily due to improvements in stent design
      • Thinner struts, easier deployment, and less thrombogenic polymers all contribute to lower stent thrombosis risk 
    • STOPDAPT2 suggested shorter duration of DAPT may provide some benefit
      • Study Conclusions: Among patients undergoing PCI, 1-month DAPT followed by clopidogrel monotherapy was superior to 12-months of DAPT followed by aspirin monotherapy at preventing major adverse ischemic events.
        • Primary outcome: death, myocardial infarction (MI), stent thrombosis, stroke, TIMI major/minor bleeding at 1 year
          • 1-month DAPT group occurred in 2.4% compared with 3.7% of the 12-month DAPT group
  • Longer duration
    • Patients to consider: 
      • Complex coronary artery disease/stenting
        • Bifurcation stents
        • Left main stents
        • Multiple stents
        • Longer stents
        • High burden of coronary disease 
      • Recurrent MIs
      • High comorbid atherosclerotic disease burden
        • Peripheral vascular disease 
        • Cerebrovascular disease
    • Risk calculators can be helpful in identifying patients who may benefit from longer DAPT duration:
      • DAPT
        • Helpful in evaluating the continuation of DAPT therapy for patients at least 12 months post-PCI procedure 
        • Provides value between -2 and +9
          • Higher DAPT scores suggest that the benefit/risk ratio with prolonged DAPT may be favorable.
          • Lower DAPT scores suggest that the benefit/risk ratio with prolonged DAPT is NOT favorable.
      • PRECISE-DAPT
        • Five-item risk score to help predict out-of-hospital bleeding during DAPT
      • PARIS 
        • Thrombotic risk score to predict the risk of coronary thrombotic events after percutaneous coronary intervention (PCI) 
    • Remember that bleeding scores miss frailty, which may portend a poorer outcome with prolonged DAPT

Pearl 4: De-escalation 

  • Refers to discontinuation of one of a patient’s two antiplatelet agents 
  • De-escalation is typically considered in patients who have:
    • Very stable ischemic profile 
    • Very unstable (high risk) bleeding profile
  • Though practice has traditionally been to discontinue P2Y12-inhibitor and continue aspirin, recent data is challenging that practice
    • The TWILIGHT study demonstrated that ASA + Ticagrelor for 3 months followed by Ticagrelor monotherapy for 12 months resulted in less bleeding compared to longer DAPT in patients who had undergone PCI with DES. 
      • The primary outcome of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 12 months for ticagrelor monotherapy vs aspirin + ticagrelor was 4.0% vs. 7.1% (p < 0.001)
  • Keep in mind that overall there is not a strong recommendation to discontinue aspirin vs the P2Y12-inhibitor, and patients will likely do well either way 
  • However, there is data to support choosing to discontinue aspirin which allows for flexibility in tailoring patient medication regimens

Pearl 5: Anticoagulation

  • Definitions
    • Triple therapy = ASA + P2Y12-inhibitor + OAC (oral anticoagulant) 
    • Dual/double therapy = ASA/P2Y12-inhibitor + OAC
  • Triple therapy is rarely, if ever, indicated beyond 1 month duration 
    • Current guidelines actually suggest transitioning to dual therapy at time of hospital discharge in patients with baseline OAC need who undergo stent placement 
  • In general, P2Y12-inhibitor is preferred over ASA, and DOAC is preferred over warfarin 
  • Show me the data: 
    • WOEST
      • Patients who were on OACS undergoing PCI 
      • Bottom Line: Double Therapy (P2Y12 + Clopidogrel) vs. Triple Therapy (P2Y12 + Clopidogrel + ASA) was associated with a significant reduction in bleeding complication 19.4% vs. 44.4% (HR 0.36; 95% CI 0.26-0.50; P<0.0001; NNT 4)
    • REDUAL
      • Compared dual therapy with a thienopyridine antiplatelet + dabigatran vs. triple therapy with aspirin, a thienopyridine antiplatelet, and dabigatran?
      • Evaluated patient with non-valvular Atrial Fibrillation undergoing PCI for CAD
      • Bottom Line: Dual therapy with a thienopyridine antiplatelet + dabigatran is associated with an 11.5% absolute reduction in major and clinically relevant non-major bleeding when compared to triple therapy. 
    • PIONEER
      • Compared low-dose rivaroxaban + single or DAPT vs. Warfarin + DAPT 
      • Evaluated patients with non-valvular Atrial Fibrillation who underwent PCI with stent placed and whether there is reduced risk of bleeding 
      • Bottom line: Low dose rivaroxaban + either single or dual antiplatelet therapy reduces the risk of bleeding when compared to warfarin + DAPT at 1 year 17.9% vs. 23.9% (HR 0.74; 95% CI 0.52-1.04; P=0.08)
    • AUGUSTUS
      • Two-by-two factorial design 
        • Apixaban vs. warfarin
        • Aspirin vs. placebo
      • Evaluated patients with Atrial Fibrillation who presented with ACS or undergoing PCI
      • Bottom line: Oral anticoagulation with apixaban was superior to warfarin(4.2% absolute reduction in major or clinically relevant nonmajor bleeding when compared to warfarin at 180 days)
        • Aspirin use in addition to oral anticoagulation and P2Y12 inhibitor therapy was associated with a 7.1% absolute increase in major or clinically relevant non-major bleeding
        • Thrombotic events were similar across both groups
  • Therefore, a reasonable general approach would be:
    • Continue triple therapy for a maximum of 1 month post-hospital discharge
    • When transitioning to dual therapy, drop aspirin and continue the P2Y12-inhibitor 
    • Choose a DOAC rather than warfarin unless contraindicated and/or cost-prohibitive

Transcript

G: Every single day in our hospital wards and in our clinics, we have to answer the question about what to do about our patients’ blood thinners.

E: Answering a simple clinical question like “should I keep this patient on plavix?” can feel paralyzing given the mountains of data we have to sift through.

G: And these are important decisions for our patients. Our choices on antiplatelet therapy impacts the risk of clinical events that everyone cares about, like heart attacks and GI bleeds. These are hard outcomes, not surrogate markers.

E: So the goal of this episode is to address some of the common clinical questions that we see when it comes to the practical management of these medications. I’m Evan Harmon, a third year internal medicine resident at UVA and future cardiology fellow. 

G: And I’m Greg Katz, a cardiologist currently working in the New York Hudson Valley. Let’s meet the guest experts who will be joining us today.

Dr. Villines: It’s an imprecise science. And so it’d be great if we could just plug in and say, okay, here’s a, an exact estimate of their bleeding risk over the next 12 months, 24 months, 30 months, etc… And here’s an exact estimate of their ischemic risk, but we just don’t have calculators that are that accurate or precise. 

E: That’s Dr. Todd Villines, a noninvasive cardiologist specializing in cardiovascular prevention. 

Dr. Ragosta: So the early stent trials, if you go read them, it was that it’s actually almost hysterical to see what they put people on to prevent clotting. They were on everything. Essentially, they threw every anticoagulant we had on a patient who got a stent.

E: And that was Dr. Michael Ragosta, an interventional cardiologists at UVA. 

Dr. Iqbal: I think of it kind of like a Seesaw, you know, the balance is the guidelines right in the middle, but you may have to tip one way or the other a little bit less or a little bit longer based on clinical factors of your patient.

G: And that was Dr. Sohah Iqbal, an interventional cardiologist at Massachusetts General Hospital. 

Let’s get started with the questions we’ll be covering today. Make sure to test yourself by pausing after each of the five questions. 

E: And remember, as Shreya always reminds us, the more you test yourself, the deeper your learning gains.  

G: Pearl 1:  Indications

E: In what patients should we consider DAPT and antithrombotic therapy?

G: Pearl 2:  Medications 

E: What are the trade-offs to consider in deciding between different P2Y12 inhibitors? 

G: Pearl 3: Duration 

E: What are the nuances of DAPT duration in different clinical scenarios? 

G: Pearl 4: De-escalation

E: Should we stop ASA or the P2Y12 inhibitor?

G: Pearl 5: Anticoagulation 

E: How do you manage DAPT in patients who also need anticoagulation? 

Pearl 1: In what patients should we consider DAPT and antithrombotic therapy?

E: Let’s dive deeper into antiplatelets. When should we be reaching for the big guns and using two antiplatelet agents instead of one?

Dr. Iqbal: So in terms of dual antiplatelet therapy for patients really in my mind, I think that you have two buckets. One is acute coronary syndromes. Um, people come in with heart attacks or, you know, warning signs of heart attacks, like I call unstable angina. Or, if they are getting a new stent or have a recently placed stent in my mind, those are really the two indications. And obviously we know those can overlap.

E: So it really helps me to think about  breaking our patients up according to the indications for DAPT: 1) patients presenting with acute coronary syndromes and 2) patients undergoing stent placement.

G: So now that we’ve gotten our breakdown, let’s start with the first category – acute coronary syndromes. Dual antiplatelet therapy is the way to treat an acute MI regardless of whether someone goes to the cath lab and regardless of whether someone gets a stent. 

Dr. Villines: So I think for optimal care, we learned, you know, if even go back to the late 1990s, early two thousands, that in patients who have acute coronary syndromes, there’s obviously a risk of stent thrombosis for those who have interventions, but even in patients who do not have percutaneous interventions, patients treated medically, we learn from trials such as, the Cure trial that CREDO and others that prolonged dual antiplatelet therapy was superior to aspirin monotherapy.

E: Right, so the CURE trial included ACS patients who got a stent and ACS patients who never went to the cath lab at all. Patients were randomized to treatment with aspirin + clopidogrel compared to aspirin alone for about a year post ACS.  This is where we learned that aggressive antiplatelet therapy up front reduces recurrent ischemic events in both ACS patients managed invasively and conservatively, and this benefit seems to persist for at least about a year. 

G: So that makes total sense when you think about the pathophysiology of patients who had an acute coronary syndrome – these patients have had an atherosclerotic plaque that ruptured. This argues there’s something different about  ACS patients than someone with stable disease. So it makes sense that more aggressive antiplatelet therapy in these patients with ACS might reduce further events, and in the CURE trial, there was a 2% absolute decrease in thrombotic events and CV deaths. 

E: Okay, so the bottom line is that ACS patients benefit from DAPT regardless of whether or not a stent was placed. And that makes sense, right? Because they are inherently pro-thrombotic, and DAPT reduces thrombosis risk. Still, it always feels like the stakes are higher after a stent has been placed. So how should we think about DAPT in these patients?

G: Ok, so DAPT after a stent feels like a loaded topic. As an internal medicine resident, I remember being told by a cardiology fellow “never stop the antiplatelet meds immediately after PCI” 

E: Yeah, this has always seemed more like a commandment than a clinical treatment 

G: It could be written on a stone tablet, and not just in the AHA/ACC guidelines. 

E: Exactly, and I think that dogma is in place for the two big risks we worry about with stents: stent thrombosis and in-stent restenosis.

Dr. Ragosta: So stent thrombosis is a sudden acute clotting of the stent. The stent is fine. The lumen is open. It’s big, it’s fine. But the stent clots. That’s stent thrombosis, it’s a catastrophic event. It can kill people. Um, and it’s pretty devastating. It happens about 1 to 2% of stent procedures over, out to a year. In stent restenosis is a more chronic thing. That is, it’s essentially what the word we use for patients is a scar tissue, which is not too incorrect… it’s intimal proliferation. So it’s proliferation of cells. That’s a response to the injury caused to the vessel wall by the deployment of a stent. That’s what drug eluting stents are designed to inhibit by having antiproliferative activity, but it’s not a hundred percent. And so patients can still develop in stent restenosis, but that’s a different presentation. That’s the return of stable angina six, eight, 12 months after their stent procedure. It’s not life threatening. It can be treated pretty effectively by a variety of methods, but it’s a very different process.

G: So to boil that down, dual antiplatelet therapy post PCI prevents stent thrombosis but NOT in stent restenosis. That’s because stent thrombosis is caused by a blood clot – meaning antiplatelet helps prevent it, which makes it different than in stent restenosis, which is caused by neointimal hyperplasia, which dual antiplatelet therapy doesn’t help that and so DAPT doesn’t prevent in stent restenosis. 

E: And we have to keep these differences between stent thrombosis and in stent restenosis in mind because we’ll come back to them in Pearl 3 when we decide how to keep DAPT going after a stent. 

G: And so before we move on from the discussion on indications for dual antiplatelet therapy, we should briefly mention a third group of patients that you’ll see on DAPT from time to time. 

E: Yeah Greg, there seems to be a subset of patients with just diffusely bad vascular disease everywhere. You know, the patients with a one liner saturated by PAD, TIAs, CVAs, CAD; the list just goes on and on.

G: That’s exactly right, so DAPT for this group doesn’t get a Class I recommendation by the guidelines, but patients with a huge burden of atherosclerosis, especially those with PAD tend to be more thrombotic. So you’re going to see DAPT for these patients from time to time. 

Dr. Ragosta: There’s reasons beyond stent thrombosis that patients benefit from DAPT and that’s prevention of other  events that are related to their atherosclerosis. And so the more athero you have, and certainly a patient has had a CABG is a high burden atherosclerosis patient, same with peripheral arterial disease and cerebrovascular disease. Those patients probably do benefit more from, you know, just kind of almost lifelong DAPT, uh, of course weighing risks and benefits of bleeding, etc. 

E: So, we just covered a lot of ground, lets recap pearl 1 

G: So dual antiplatelet therapy has a role in three different groups of patients: 1) Patients who have acute coronary syndromes regardless of whether or not they go to the cath lab or regardless of whether or not they get stents 2) Patients who get stents regardless of whether or not it is in the setting of an ACS 3) Vascular disease in multiple, different vascular beds and a high thrombotic burden. 

Pearl 2: What are the options for DAPT in addition to aspirin? What is the second anti-platelet drug? 

E: Okay, Greg, so when we’re putting patients on antiplatelet medications, which P2Y12 inhibitor should we be reaching for in addition to aspirin?  

G: This decision comes up all the time in both the inpatient and outpatient setting. We have three oral P2Y12 inhibitor choices: Clopidogrel (or Plavix), Prasugrel (or Effient), and Ticagrelor (or Brillinta).

E: A good way to weigh the pros and cons of each P2Y12 inhibitor is to think about 3 things: its potency, its bleeding risk and its feasibility

Dr. Villines: We prefer today, if you look at the different agents available, um, there are some advantages to using P2Y12 inhibitors that aren’t not clopidogrel. Um, and, if you just think about the issues that we have with clopidogrel or that it’s kind of a messy drug and the sense that it is, um, a pro drug, it requires a really two step metabolism to reach its active state. 

E: So basically because clopidogrel has that two-step metabolism its gonna take some time for platelets to be fully inhibited.

Dr. Ragosta: Acutely, what you want is you want a very rapid onset action agent and, uh, Plavix is not that agent, right? So if you load someone with 600 milligrams of Plavix in a STEMI, you’re not going to have efficacy of that drug for many hours and it’s kind of beyond the point where you want that. Ticagrelor and Prasugrel are faster on, but even then they may not be adequate. And remember, you’re relying on oral absorption of a drug and, and there’s a lot of evidence about STEMI patients in particular, having delayed motility and delayed absorption.

G: And it’s not just the rate of platelet inhibition that we’re thinking about, there’s also the concern about whether every patient of ours responds to clopidogrel in the same way. 

Dr. Villines: There’s a lot of variability in the genetics, um, and how clopidogrel is metabolized as well as it has a lot of drug drug interactions.

G: You might have heard of a patient who is “plavix resistant” and that some ethnic groups have a slightly higher incidence of not responding to the drug. These variations seem to be related to genetic variations in clopidogrel metabolism.

E: I think some hospitals even use point of care genetic testing for all of their ACS patients 

G: Some hospitals certainly do that, but this genetic testing has been tested in RCTs.  The interesting thing, though, is that while it’s certainly not worse to use a genotype guided strategy to guide your antiplatelet agents, it isn’t clear from the data that it’s a better way to choose your P2Y12 inhibitor.  

E: Sooo, you’re saying I shouldn’t bring my 23 and me results to my cardiology appointment? Would’ve been nice to know that ahead of time. 

E: Anyway, all this stuff about clopidogrel metabolism is interesting, what we really care about is how good are these drugs in treating and preventing ischemic events. So, how effective is Clopidogrel compared to Prasugrel and Ticagrelor?   

Dr. Villines: It tends to be just slightly less potent as compared to Ticagrelor or as compared to, um, uh, Prasugrel.  there’s clinical trial data showing that there’s a benefit, for example, if you use a Ticagrelor or Prasugrel, um, in patients who come in with acute coronary syndromes, particularly those who are undergoing PCI, um, but in, in case of Ticagrelor, regardless of whether you get PCI. So, so that is, that is, you know, we prefer to use those agents. Um, there is a slight increased risk of bleeding.  And so, you know, you have a patient who has a really high bleeding risk. We will tend to use Clopidogrel versus a patient who we think has a low bleeding risk and a high ischemic risk. We would much prefer to use one of the other P2Y12 inhibitors. 

G:  We have randomized clinical trials like TRITON TIMI 38 and PLATO to show the difference here. These trials took an ACS population to comparing Prasugrel to Clopidogrel, the other Ticagrelor to Clopidogrel – And story is the same for both them. The more potent agents, Ticagrelor and Prasugrel, reduce ischemic events at the cost of increased bleeding risk. 

E: Okay, so if you haven’t gotten it by now, Ticagrelor and Prasugrel are your higher potency antiplatelet options and to be more precise these trials found about a 2-3% absolute difference in ischemic events when compared to Clopidogrel. But how do we choose between them? 

G:  We didn’t have a head to head data to compare them until 2019 when ISAR-REACT 5 trial was published. This trial compared Prasugrel to Ticagrelor in ACS patients and found that Prasugrel reduced ischemic events more than Ticagrelor did with similar bleeding risk profile. 

E: Really, that’s really surprising to me Greg because I always thought that Prasugrel of having the bad rap for bleeding. I thought it had a black box warning in patients with prior strokes due to the concern for intracranial hemorrhage.

Dr. Iqbal: Prasugrel data was a little more concerning because the risk of bleeding was considered higher as compared to Clopidogrel. So I think there was a trend in the interventional community to start using Tricagreol a little bit more. And now you have this, this study that suggested Prasugrel may be better, potentially, in these patients post ACS post PCI.

G: To be honest, I’m not sure exactly how much ISAR-REACT 5, or any one clinical trial for that matter, should be changing our clinical practice. And something about the big picture conclusion doesn’t pass the smell test for me. I don’t understand the free lunch here that you can prevent ischemic events and not increase bleeding risk simultaneously. 

E: And speaking of bleeding risk, sure there’s drug-specific bleeding risk to consider, but what bleeding risk does the individual patient bring to the table and how do we evaluate that? 

Dr. Iqbal: So, people throw around the term high bleeding risk. And I do think that it can be confusing as a catch all phrase. So in my mind, you’re either thinking about patients that have had a bleed prior, when we think about high-risk bleeding or you’re thinking about what are their risk factors and age definitely comes to mind, prior stroke or prior bleed comes to mind, maybe not active. Other things that we think about are kidney disease, which actually is complex, because it also is a high risk category for ischemic events. So I think, and anemia, you know, thinking about DAPT, I always look at people’s hemoglobin and their MCV and what potentially could their bleeding risk be there. So, it is a catch all phrase and it does require a little bit more thinking than just there’s a lesion and I’m going to stent it.

G: I think that people are going to be surprised to hear an interventional cardiologist looks at the MCV.

E:  I guess sometimes the smear is more important than the stent after all, Greg. But there are so many times where we come up with this great drug regimen really thinking hard about someone’s ischemic risk or their bleeding risk just like Dr. Iqbal just mentioned… but then there is actually the patient sitting in front of us… That’s where it gets tricky, because how much does that drug actually make sense for that individual patient?

G: So, take the example of Ticagrelor in our patients. Adherence can be a challenge here. I often talk to my patients about the fact that Ticagrelor has twice daily dosing, and tell them that you need to be honest with me and honest with yourself if a twice daily med will be too hard to take.  I also caution them that if you get a little bit short of breath, you can’t just stop your medications and thats because 10% of patients on ticagrelor can have this adenosine mediated dyspnea.

E: The other big side effect to remember Greg is the impact on patient’s wallets — these meds can get pretty expensive.

Dr. Villines: Um, so insurance coverage is one of the first questions we ask is can a patient afford this? What’s the copay. I mean, these are real life questions and it makes no sense to put someone on a medicine if there’s no way they can afford it when the differences that I just mentioned are small. 

E: Just from a quick google search, even with Good RX, which should make things cheaper, I was surprised to see Ticagrelor still costs upwards of $400 a month whereas Clopidogrel is way cheaper at about $20 bucks. Prasugrel falls somewhere in the middle, around $200-300, but maybe at the small cost of intracranial hemorrhage. 

G: Oof, I think that’s a little bit rough. So while it’s always good to remember the black box warnings for medications that we prescribe, I still do use Prasugrel in my patients. The key thing to know is say you have a patient who comes in and they’re on an expensive medication they can’t afford that you need to switch them. And you should remember that every time you switch P2Y12 inhibitors, you must reload with the new agent. 

E: And for help navigating that tricky transition, we’ll include a link in our Show Notes with a nice graphic from Circulation 

G: That graphic is really outstanding. This is a great time to summarize pearl 2. We can think of clopidogrel as the least potent P2Y12 inhibitor, but also has the lowest risk of bleeding. On the other end of the spectrum, prasugrel is probably the most potent, but has the highest risk of bleeding, including life-threatening bleeding. Ticagrelor is kind of the middle man both with respect to ischemic and bleeding risk. These decisions absolutely have to be tailored to individual patients. Since the differences are small here – we’re talking about 2% absolute risk reductions – most patients will do well no matter what you choose. 

Part 3: How long do you keep patients on DAPT? 

G: So we’ve covered indications for DAPT and the pros and cons of the available P2Y12 inhibitors. But we haven’t talked at all about duration. 

E: Yeah Greg, so it seems like patients are always asking: how long do I need to take these medications for? 

G: They’re asking every single day in clinic! The answer about duration is really a moving target depending on which patient you’re considering and which trial you reference. You may remember from Pearl 1 that we’re using DAPT to prevent two major outcomes: stent thrombosis and de novo ischemic events. And so the first thing to know is there’s been a lot of improvements in stent design over the years. 

Dr. Iqbal: So, the first generation stents were kind of these big bulkier stents with the first iteration of a drug-eluting polymer. And there was some suggestion from registry data that potentially these drug eluting stents would have a higher risk of stent thrombosis. But, stents have really evolved over time. There’s the second iteration. And even, you know, multiple third iterations where we have thinner metal struts, we have less metal because now we have an open cell design where, you actually have some give in the stent, there are much more deliverable. 

G: So in 2003 we were really worried about stent thrombosis with even a short pause of antiplatelet therapy. Stents today just don’t have the same thrombotic risk 

E: And for anyone who finished training more than a few years ago, this represents a huge shift from what you learned in residency. 

G: It’s a really big deal. Very short term DAPT doesn’t seem to increase the risk of stent related complications with the current generation of stents with the current generation of stents. We have RCT evidence from STOPDAPT2. To show that there isn’t a significant risk of stent thrombosis in post-PCI patients who received DAPT for just 1 month followed by Clopidogrel monotherapy. And even with just one month of dual antiplatelet therapy, the rate of stent thrombosis is just incredibly low – about 0.1% just incredibly low

E: Yeah that is so low but that short of a duration of 1 month is just so surprising to me. I knew there were studies with good safety outcomes for 3 and 6 month courses for DAPT post PCI but man, just 1 month?!

G: Yeah, 1 month does feel really short. But you have to keep in mind that a very short course of DAPT isn’t right for every patient. For example, I always consider whether the stent was placed for an acute coronary syndrome or stable ischemic disease. Not to beat a dead horse, but I feel compelled to re-emphasize that patients who had ACS are at much higher thrombotic risk. And then there are other things to consider:

Dr. Villines: What’s the size of the stent? How many stents did they have placed? Um, how much coronary disease do they have outside of their stinted segments? Did they present with an acute coronary syndrome or not? Because that often does sometimes change our duration of therapy. And then sometimes even down into the details about, you know, what, what, what type of stent procedure did, did they have, did they have a complex, bifurcation, stenting? Did they have a very short stent of a large diameter in a relatively distal vessel?

G: And that’s why I look at the cath report for  all of my patients with stents, because it tells us about procedure specific factors that make you think of a longer course of DAPT. And there are also patient specific factors that we need to consider.

Dr. Villines: And then what else do we know about the patient? What do they have peripheral arterial disease? Do they have other ischemic risk factors? Have they had prior ischemic events, either stroke, TIA, peripheral arterial events, um, how much coronary disease burden do they have? That’s a really complicated answer, but it really is not a one size fits all approach. And so, you know, to boil it down, it’s, you know, what event that they have and when, what is their residual ischemic risk based on some of those risk factors I just mentioned, and then what is their bleeding risk? 

G:  There is definitely a lot to consider. And to form an easy reference, we’ll have all of this information available in our show notes online. 

E: I feel like that’s a pretty good checklist to consider for each patient when thinking about stopping DAPT. But  let’s say everything seems to be going fine on DAPT- my patient doesn’t need an urgent surgery or a bleeding complication – so in those patient, how long should we continue for those patients?

G: I find it really interesting when thinking about the optimal duration of DAPT to go back and look at all the Kaplan Meier curves from the DAPT in ACS trials – CURE, TRITON, PLATO, ISAR-REACT 5 – because they have the same pattern. Theres a big reduction in ischemic endpoints that’s  seen early on – within the first couple of months – and then there’s an ongoing curve separation long term. So, the story I get from all of these interventions is the same – aggressive antiplatelet therapy up front has the biggest risk reduction in ischemic endpoints and then long term you continue to get a marginal benefit from continuing the more aggressive regimen. The bleeding story is identical. Risk is highest up front and then increases marginally over the long term.

E:  That’s a really interesting point about that ongoing separation of the Kaplan Meier curves over time, I had never really considered that. But I think all of those trials were looking at just the first 12 months: Long-term, after we’d had our patients on DAPT for over a year, what happens then?

Dr. Ragosta: There was the trial that looked at really prolonging DAPT out to three years, you know, those patients had benefit albeit at a higher bleeding, uh, cost. Um, but those weren’t stent thrombosis events that they were preventing late. It was other kind of MI’s stroke, you know, cardiovascular events. So prolonging duration or indefinite duration in the high burden atherosclerosis patient is a, is a benefit. And I think that’s a lot of my patients. I tell them, “Look, you’re doing fine., you’re not bleeding. If I were, you I’d stay on this stuff forever.” Now, it’s easier than interrupting it, right at that point, you know, you can be more cavalier about, okay, you need to have colonoscopy, go ahead, stop it for a week. No big deal go back on whenever after. But I think having them on that as a preventative or, um, you know, kind of prophylactic measure for preventing events is beneficial.

G: It gets complicated quickly. Sometimes it’s just easier to think about the ideal duration of DAPT based on the indication and what the guidelines say and then adjust up and down based on individual patient characteristics.

Dr. Iqbal: So after someone has an acute coronary syndrome, the optimal duration of dual antiplatelet therapy is 12 months. Again, that will need to be tweaked. If you think someone has a high bleeding risk or a high ischemic risk, but the ideal is 12 months. So the optimal duration of dual antiplatelet therapy in someone who had a stent for stable ischemic disease is six months. At this point, the guidelines suggest six months. I will say that that is a moving target because we have lots of data coming out that it could be shorter, but at present, I encourage patients to stay at least six potentially nine months. And, uh, go from there when I think about what kind of bleeding risks they have versus ischemic risk. If they have very low bleeding risk, I do still continue patients up to 12 months, but I think that’s leftover from practicing for the last 12 years. 

E: Oh that sounds so straight forward but in clinical practice, these decisions can feel not so straight forward. It seems like a great tool to have would be, I don’t know, a prospectively validated risk calculator for a patient’s ischemic and bleeding risk. 

Dr. Iqbal: So there are a couple DAPT calculators that have been created from retrospective data, uh, that allow us to understand someone’s bleeding risk. Uh, some of those are DAPT, PRECISE DAPT and Paris. So those have a lot of factors in them their age, their hemoglobin, their kidney disease.

E: At least for me, I do find these risk calculators – the DAPT score and the PRECISE DAPT score useful. They’re just a quick google search away to help me quantify my gut feeling on someone’s bleeding risk.

Dr. Iqbal: So, when you do look at the risk calculators, it’s important to know what factors they use to develop them. And then again, this is true for all trial data. You have to think of what age group were they using it in. Sometimes there is you know, an age cap of 85 and now you have this 90 year old. So it’s kind of how do you use your patient and how do they fit into the data.

G: I’ll add one caveat here. A really important characteristic that hasn’t made its way into calculators is frailty. Frail patients have worse outcomes with all of our interventions, so I tend to stop blood thinners earlier in those patients

Dr. Iqbal: So there are some patients that fall out of the risk calculators, uh, and sometimes you just look at them and you know, that they may have a high bleeding risk, but you can’t find their predictors in a risk calculator. And in my mind, those are people that are frail though. BMI comes into one of them. Those are people that I think this, the social, the social factors are completely missed. Here are people maybe take too many, may not have access to follow-up care the way that we would want.

G: I’ve also learned that how you frame this conversation to the patient matters quite a bit for their anxiety level when they leave the appointment.  I tell patients, “Look, if we continue your blood thinner, you’re probably not going to have a bleeding problem, and if we stop your blood thinner, you’re probably not going to have a heart attack. But we’re balancing risks of blood clots and bleeding complications – and a decision needs to be made. On some level, part of the choice depends on your preference for which risk you’d like to take.” 

E: Yeah, and that makes sense because if you look at all the data we just went through, a lot of event rates or the absolute differences between groups are actually really small. I’m curious Greg, what do the patients say when you frame it like that?

G: A really tiny minority have a real preference, but most of them say – “I’ll do whatever you think is best, doc”

E: Great, so much for shared decision making. Alright, so to give patients like these the best advice possible, let’s recap our framework on DAPT duration: there are four big points we want to consider:

  1. A stent placed today is much safer than a stent placed 15 years ago when it comes to thrombosis risk

  2. G: We should think of patients who had ACS as much higher thrombotic risk than non-ACS patients. We tend to keep DAPT on in patients who had ACS for 1 year vs. we may feel more comfortable stopping it earlier for pts who had stable ischemic  disease, at around 6 months. This is a moving target, though, since it’s a place where the guidelines haven’t yet caught up to the latest trials establishing safety of 3 and 6 months DAPT courses.

  3. When we’re deciding duration of DAPT, it’s  helpful to look at the cath report and look for higher risk features: bifurcation lesions, left main stents, multiple stents, and high burden of coronary disease should all make you more hesitant to stop DAPT without a compelling reason

  4. G: Risk calculators help us in two ways: 1) Remind us what clinical characteristics influence bleeding and ischemic risk 2) provide a semi-quantiative framework to analyze our decision. Let’s not forget, there are patients that fall through the cracks, particularly our frail patients.

Pearl 4: Should we stop ASA or the P2Y12 inhibitor?

G:  So eventually in each patient’s trajectory you get to a point where you have to decide to stop the second antiplatelet agent. At the point you are implying that the patient is either 1) stable enough from an ischemic standpoint or 2) high risk enough from a bleeding standpoint to merit de-escalation.

E: So do you stop the ASA or the P2Y12 inhibitor?

Dr. Iqbal: So there is a lot of data about the fact that we may be able to drop aspirin. And I think this is really interesting and thought provoking data, and it hasn’t fully come into clinical practice or changed guidelines yet. 

E:  So Greg, I’ll be honest, I can’t say that I’ve ever really stopped someone’s ASA. There is something about a “baby aspirin” that to me feels like a less risky blood thinner than the other agents.

G: Its not just you. I’ve had patients who are totally unwilling to take a blood thinner but very happy to be on aspirin. Patients also like just being able to go to the pharmacy and pick up a bottle of baby aspirin rather than filling a prescription. But it’s interesting – let me ask you a question. Do you think of Aspirin and P2y12 inhibitors as having the same mechanism of increasing bleeding? 

E: I think of them as different, especially with regard to their mechanism, right? Aspirin is an indiscriminate COX inhibitor, blocking prostaglandin production, so your GI tract loses some protection. 

G: Exactly, so they both cause platelet inhibition but aspirin has a second bleeding hit because it also hurts the GI mucosa. Interestingly, there’s some data from the CAPRIE trial to back up that alleged double hit bleeding mechanism of aspirin. You’ll see the suggestion in CAPRIE that Clopidogrel actually has a lower bleeding risk than Aspirin, albeit a 325 mg dose instead of 81mg.

E: Isn’t that surprising because so much of our practice is to stop the P2Y12-inhibitor and continue the aspirin

G: I think some of that is just clinical inertia. And the TWILIGHT Study actually might make you feel comfortable doing the opposite and actually stopping the aspirin instead. This trial stopped aspirin 3 months post PCI in patients with high ischemic risk, including some ACS patients. We saw that patients did pretty well from an ischemic perspective, stopping the Aspirin and continuing the Ticagrelor even in this high risk group.

E: That sounds pretty compelling, Greg, but I guess i’m wondering then why isn’t everyone changing their practice and stopping the aspirin?

G: No. Does any one trial ever change everyone’s practice?  And everyone decides on the single agent a bit differently – even the guidelines don’t firmly tell you which one you should keep. 

E: So just to summarize Pearl 4, the thing I will take away is we don’t need to stress too much about stopping the ASA or the P2Y12 inhibitor. Your patient will probably be fine regardless and there is data to support either ASA or the P2Y12 inhibitor.

Pearl 5: How do you manage DAPT in patients who need anticoagulation? 

E: Well, Greg, we’ve covered a ton of ground this episode, but I think this last pearl is an important one: What do we do with patients who need antiplatelet therapy AND anticoagulation? 

G: I think about the challenge of managing antiplatelet therapy with anticoagulation every single day. Think about how many patients you have who have Afib and CAD, or prior stent and DVT in the past. This is a challenge that isn’t going anywhere, and we need to think about how to manage these patients appropriately. Do you send them a home, on triple therapy which means ASA, P2Y12 inhibitor and anticoagulant, or some other combination of antithrombotic medications? 

Dr. Villines: So if you had a recent PCI, whether that PCI was for acute coronary syndrome or not, when you take triple therapy, your bleeding risk really, really rises significantly. And I think the consensus is that there is a sweet spot for, for combining anticoagulants and antiplatelet therapy and that you can go, uh, you know, you can go to a point where you’re getting more bleeding and less ischemic benefit.

G: As Dr. Villines alludes, we’ve had alot of trials to help guide this decision. The first place to start is the WOEST trial from 2013,which randomized patients who were already on warfarin and underwent a PCI to single antiplatelet therapy versus dual antiplatelet.  The combo of just one anticoagulation with warfarin and a one antiplatelet agent  had way  fewer bleeding events with no signal for increased thrombotic risk.

E: Okay, that makes sense, especially considering patients were being anticoagulated with warfarin. That’s basically begging for a bleed, right? Most of the patients we see today are on DOACs.

G: Well, that’s part of the reason that after WOEST came REDUAL, AUGUSTUS, and PIONEER. We have data to show us that whether you’re using dabigatran, apixaban, or rivaroxaban, you’re probably fine stopping the aspirin and continuing clopidogrel with a DOAC of your choice.

Dr. Iqbal: I think how we do this is kind of interesting. Uh, there is a trend towards keeping people on triple therapy for potentially their hospital stay potentially one week, potentially one month. And I’ve always found that trend. Interesting, and really try to scour the data to say, do we have suggestion for that?

E: Triple therapy is something we often do, but there really isn’t great evidence for it. But long-term, we should really be defaulting to a single antiplatelet agent with an anticoagulation agent unless there’s a really compelling reason not to. 

G: And those compelling reasons for potential triple therapy might be an acute coronary syndrome with multiple stents or bifurcation stents, high thrombus burden, or a patient who has recurrent MIs with a super high ischemic risk.

E: Alright, Greg, so if I’m ready to break away from triple therapy, two questions come to mind: First, which antiplatelet agent are we going to drop? And second, how long should we continue single antiplatelet + anticoagulation therapy? 

G: The only regimen that’s been tested is dropping the aspirin and continuing the P2Y12. And the P2Y12 that’s been best tested in Plavix. 

E: Really that’s the only regimen that’s been tried? It’s so interesting to think about how so much of what we do is based on what cut offs or choices of drugs were used  in clinical trials. So with that in mind how long are we keeping patients on the P2Y12 inhibitor plus anticoagulation?

G: So when you’ve made it 1 year post ACS, or probably 6 months post stent for stable ischemic disease, you’re probably fine stopping all antiplatelet therapy and continuing anticoagulation alone. 

E: Well I think we can wrap this pearl up 5. When it comes to triple versus double therapy, less is more.  Drop the aspirin, avoid triple therapy, and limit duration. 

G: And that’s a wrap 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! 

If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on instagram or facebook page. Thank you to our peer reviewer Sunny Intwala. Thank you to Max Had for the audio editing and Rioka Hayama for the accompanying graphics. And thank you to Vickie Kassapidis for off-air producing this episode. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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