Time Stamps

  • History matters – how symptoms match up to pathophysiology [2:30]
  • Vulnerable plaque vs. progressive atherosclerosis: the same or different? [5:11]
  • High sensitivity troponins and the future of unstable angina – should it still exist? [7:36]
  • Risk Stratification Redux – how to determine who needs a “cath” [9:45]
  • Review of teaching points [12:24]
  1.  

Show Notes

  • Dr. Braunwald, Cardiologist of TIMI score fame, classified unstable angina (which he lumped together with NSTEMI) into three clinical syndromes and four underlying pathophysiologies. We focus on two clinical syndromes that match up with specific pathophysiology:
    • The first syndrome is new onset or worsening angina, called crescendoing angina. This worsens over days to weeks (sometimes months), and should not be severe enough to occur at rest.
      • Crescendoing angina can be attributed to increasing coronary artery luminal narrowing caused by progressive atherosclerosis. This causes a cholesterol plaque with a thick, stable, fibrin-rich cap, sometimes called a “red” plaque/thrombus.
    • The second syndrome is angina severe enough to occur at rest within 48 hours of a patient presenting to care. This corresponds to a vulnerable plaque that has ruptured and developed a non-occlusive thrombus.
      • This underlying etiology is more acute and unpredictable than progressive atherosclerosis, so thought to be more dangerous. It is called a “white” thrombus because in acute plaque rupture of a thin immature cap, we see accumulation of white platelet-rich thrombus.
  • These two syndromes also correlate with results on coronary catheterization. One study showed that one third of patients developed an MI occlusion at the site of prior severe atherosclerosis, so presumably due to progression of disease. The other two thirds of patients developed occlusion at a site with only mild CAD, so likely to rupture of an unstable plaque.
  • High sensitivity troponins are changing the game. Many cases that were previously trop-negative and classified as unstable angina are now mildly troponin-positive so being reclassified as NSTEMI. At some point, the diagnosis of UA may disappear, but it hasn’t yet!
  • The TIMI score (and others) can be used to estimate which patients with UA or NSTEMI are actually high risk and would benefit from early cardiac catheterization. 
  • A TIMI study showed that low risk (e.g. low score) patients, often those with unstable angina, did not benefit from early catheterization, where as medium or high scoring patients do.
  1.  

Transcript

S: Welcome back guys! Let’s get back to troponins and the terrible, horrible, no good, very bad unstable angina.

J: C’mon Steve we need more of an intro than that.

S: Well you wouldn’t let me sing My Heart Will Go On, and Shreya banned further obscure movie references.

J: Haha fine. And for anyone that missed our last episode, we suggest listening to it now; someday we’ll probably release one where the puns and movie facts are edited out. But for now you’ll have to suffer through it.

S: Or maybe we’ll have one with more edited in?

J: Nononono. Ok, so we’ll give you a quick second to check out our last one …

S: … long enough? Great, and welcome back to those of you that went back to part 1. Puns and all. Last time talked about key concepts in ACS or acute coronary syndrome. Like what is unstable angina and why we should care?

J: More specifically, we covered why we like to talk about and use the TIMI score

S: Along the awesome CARAT 65 mnemonic.

J: No more mnemonics Steve! And how we use scores like TIMI to determine if a patient with unstable angina is at high or low risk of MI or death?

S: So today we’re going to quit playing games with the HEART score and let us show you the shape of the heart.

J: No backstreet boys today please

S: Words never uttered in a civilized society. But seriously, I thought we could talk about pathophys today.

J: Anything but your singing!

J: Hi, I’m Janine Knudsen

S: And I’m Steve Liu

J: Welcome to Mind the Gap

S: And our second episode on unstable angina

J: Again, many thanks to Dr. Norma Keller, Chief of Cardiology at Bellevue Hospital and Assistant Professor of Medicine at NYU, for peer-reviewing this episode.

S: And don’t forget to check out the brand new CoreIM website – coreimpodcast.com – for tons of great med-ed tools and podcasts.

J: What a smooth shout out to #FOAM! Today we’re going to take our conversation about unstable angina to the next level.

S: We’re going to cover 1) why it’s important to interview our patients about the history of their chest pain, and how that relates to the pathophysiology of unstable angina  

J: And 2)  how have high-sensitivity troponins changed the way we think about ACS?

S: And finally 3) how can we use both clinical history and pathophys to risk stratify patients and determine management? You think there is a score for that?

J: So Steve I know you like to take deep dives into history. Are we going to do that today?

S: I’m glad you asked Janine. We can’t talk about unstable angina without talking about how Dr. Eugene Braunwald who wrote tons of super important articles on unstable angina.

J: It’s important to note that when he wrote about unstable angina in the 1990s, he used it as a catch all term, including both patients with positive biomarkers

S: What we’d now call NSTEMIs

J: And patients with negative biomarkers

S: What we now call UA.

J: And so in that context, Braunwald published a seminal article in Circulation called: “Unstable angina: a classification.”

S: This began a decades long journey which we will now try to summarize into a description of pathophysiology and clinical syndromes.… in about 5 minutes

J: Braunwald tried a few ways of categorizing patients to figure out who was high risk of MI and death, based on clinical history and pathophysiology

S: As a tie in to our last episode, Braunwald and his group quantified this risk in the UA/NSTEMI TIMI score.

J: So today, we’ll first go through the clinical histories and then we’ll connect them to the pathophys. We recommend checking out our graphic on the coreim website for you to follow along.

S: Braunwald describes three types of chest pain severity – basically 3 different types of histories you could get from a patient coming in with chest pain. But we only really care about two of them.

J: Ok so the first type of chest pain is new onset or worsening angina symptoms, but no chest pain at rest.

S: This is sometimes called crescendoing angina.

J: Braunwald later connected these symptoms to the pathophys of progressive mechanical obstruction, which is from “severe, organic luminal narrowing” such as progression of coronary atherosclerosis.

S: Which depending on the clinical context, can be either slowly progressing, like in the course of weeks to months

J: progressive stable angina

S: or it can be rapid in onset, like the closure of an already critical lesion, causing an MI

J: The second type of chest pain is angina at rest within the past 48 hours.

S+J: Aka The Danger Zone.

S: This corresponds to the pathophys of non-occlusive thrombus that develops on pre-existing disrupted plaques…

J: It’s partially occlusive, so not a full STEMI which is a caused by a complete thrombotic occlusion

S: Just to be clear, we’re not covering 2 of the types of pathophys that Braunwald included in his classification.

J: Those are dynamic obstruction like prinzmetal’s angina, and demand-type anginas, like type II MI from inflammation or infection.

S: We also omitted his third clinical syndrome of chest pain, which is CP at rest that resolves at least 48hrs before presentation… because it doesn’t fall into the definition of ACS

J: Cause it’s just not that acute…

S: So back to those two clinical syndromes and pathophys – es – you might be wondering, why do they matter? Don’t both causes lead to cardiac ischemia? Aren’t they both just BAD?

J: Well, Braunwald’s argument was that slowly progressing plaque, causing crescendoing angina, was somewhat more steady and predictable.

S: Whereas chest pain at rest from a non-occlusive thrombus on a disrupted plaque is unpredictable and more dangerous. It can clot off at any time causing a total occlusion or STEMI.

J: These 2 different pathophysiologies also look different on cardiac catheterization.

S: There’s a really interesting study called “Coronary Plaque Disruption” that gets at this.

J: They looked at patients who suffered an MI, but actually got a cath beforehand.

S: A third of them had preceding obstructive coronary disease at the site of their MI, meaning that their infarction was probably due to rapidly progressive luminal narrowing of their known obstruction.

J: The remaining two thirds had only mild CAD on their previous catheterization. So their MIs were probably due to unpredictable rupture of that small but vulnerable plaque.

S: How sad and lonely.

J: Aww. They’re just misidentified and misunderstood.

S: Niiice. Let’s get even nerdier and go back to our basic science days. I remember being tortured by discussions of two types of thrombus.

J: You may have heard these called red thrombus for “fibrin rich” and white thrombus for “platelet rich”

S: In progressively worsening atherosclerosis we see a thick fibrinous cap on a growing plaque. This is called red or fibrin-rich thrombus.

J: In acute plaque rupture, we’ll more likely see an vulnerable plaque with a thin, immature cap, covered by white or platelet-rich thrombus.

S: It’s like a teenager going through its awkward growing pains – its young and doesn’t know any better.

J: So we’ve now given you two classifications of chest pain, with their presentations, pathophys, and plaque/thrombus type.  

S: The prior study we discussed with pre-MI caths found a 2:1 ratio of plaque rupture vs. progressive luminal narrowing. This is relatively close to what Braunwald reported seeing at the clinical level based on patient symptoms.

J: And patients with plaque rupture are more likely to be sick. Braunwald found that one third of these patients will present with a positive troponins. Compare this to only 10% of patients with crescendo angina.

S: So symptoms and underlying pathophys really correlate. How cool!

J: But briefly here’s one thing to consider: with both of these pathophyses because you get some occlusion of the coronary artery, you’d probably get some myocardial ischemia. So in this day and age, you’d expect an ultrasensitive troponin will be positive.

S: So you’re saying that all of these patients would now be classified as NSTEMI?

J: Well interestingly, there still seems to be a subset of patients with classic symptoms of ACS that for whatever reason, don’t have a positive troponin, and that’s even despite cath findings consistent with coronary artery occlusion.

S: Braunwald addressed this exact dilemma in his 2013 article with David Morrow, aptly title “Unstable Angina, Is it time for a requiem?

J: It’s really good! Braunwald and Morrow describe the trajectory of unstable angina. Initially it was meant to represent the zone between stable angina and an MI.

S: But over time, as we became better and better at detecting troponin, more cases got reclassified as NSTEMI instead of unstable angina. So the percentage of patients with ACS who fall into the bucket of unstable angina has shrunk significantly.

J: And they almost suggests that in the future we might discuss removing the diagnosis of unstable angina altogether! To paraphrase the paper’s conclusion “… we have now come full circle in our definition of symptomatic ischemic heart disease… patients with ischemic heart disease will now be divided into the original two … groups … angina pectoris… [and] acute MI.”

S: Some cardiologists even propose that maybe cardiac markers become the only definition for ACS going forwards, but it’s very unlikely. Combining our quantitative tests with our qualitative clinical history is still important.

J: And we should be clear, WE are not saying flat out that unstable angina doesn’t exist. We’re just enjoying these debates..

S: The rise of high sensitivity troponin should just make us think twice when we meet people with chest pain syndrome but negative troponins.

J: So let’s bring this home, Steve. All this pathophys and troponin stuff aside, what do we actually do with the patient in front of us? Should we page Cardiology and ask them to urgently take the patient to the cath lab?

S: What if we risk-stratified patients and use that to guide our decision making?

J: So let’s circle back to the TIMI score from our last episode, which we apply to patients with unstable angina or NSTEMI to estimate their risk of a major adverse cardiovascular outcome or MACE in the next 14 days.

S: What we haven’t mentioned yet, is how we use it to guide clinical management if we want to cath.

J: It turns out, patients with moderate to high risk, so TIMI scores of 3 pts or higher, may benefit from urgent cardiac cath.

S: This comes from TACTICS-TIMI trial brought to you by who else but Dr. Braunwald’s TIMI group, which randomized about 2200 patients to early cardiac cath or not.

J: The control group still got cathed if they didn’t improve on medical therapy alone, or if they had a positive stress test.  Both groups got treated with antiplatelet and cholesterol lowering medications.

S: The trial showed that patients who got early catheterization had better primary outcomes of death, MI, or rehospitalization for ACS in 30 days. Remember that combined outcome is also called MACE.

J: The MACE rate was 7.4% in the test group vs. 10.5% in the control group, which equals an absolute risk reduction of 2.1%. And this effect persisted at 6 months with MACE rates of 16% vs. 19%.

S: Weirdly enough, this was all driven by MI and rehospitalization outcomes. The mortality rate did not actually differ between the two groups.

J: And also interesting is that just because patients got cathed, it doesn’t mean they got revascularized. Only 60% of patients in the intervention group got a stent or a CABG vs. 36% in the control group.

S: It’s important to note that there was one subgroup that did NOT show a benefit from early revascularization compared to control.

J: It was the 25% of the study population that had negative troponins and fell into the gray zone of unstable angina – this is particularly true for women. This group had no clear improvement in outcomes with early cardiac cath.

S: For these folks, those with UA, the study suggests performing a stress test after stabilization to help determine if their chest pain really was from coronary occlusion. If not, they probably don’t benefit from revascularization.

J: To summarize, the TIMI score is a tool to identify high and low risk groups, aka those who benefit from rushing to the cath lab in the first 48 hours vs. getting a stress test for more information first.

S: But full disclosure the AHA guidelines suggest using the GRACE score instead of the TIMI score.

J: We’re just using figured we were all more familiar with TIMI score so are using it an example to make our point about risk stratification.

S: OK that was it for today so let’s recap. We reviewed a few different angles through which you can view unstable angina.

J: 1) clinical symptoms correlate to pathophysiology, cath findings, and even outcomes.  A patient with slowly worsening atherosclerosis and progressive anginal symptoms is lower risk than a patient with an unstable, disrupted plaque causing angina at rest.

S: 2) high sensitivity troponins may completely change how we think about classifying ACS. But we’re not ready to get rid of unstable angina just yet. Just know that most patients who previously would have had UA are now getting reclassified as NSTEMIs. 

J: And 3) in our last episode we talked about how quantitative scores can help you decide who not cath, but both the TIMI and HEART scores can also be used to anticipate who might benefit from revascularization.

S: Patients classified as moderate or high risk should have some benefit from early cardiac catheterization, whereas low-risk patients will not, based on the TACTICS-TIMI trial.

J: Those low-risk patients, mostly patients with unstable angina, should get a stress test after they’re stabilized to risk stratify them further. So that’s all for our episode!

References

  • Braunwald E. Unstable angina, A classification. Circulation. 1989;80:410–414
  • Braunwald E. Unstable Angina: An Etiologic Approach to Management. Circulation. 1998; 98:2219-2222.
  • Falk E, Prediman KS, Fuster V. “Coronary Plaque Dispruption” Circulation. 1995;92:657-671.
  • Hamm CW, Braunwald E. “A classification of unstable angina revisited” Circulation. 2000;102:118-122
  • Braunwald E, Morrow DA. “Unstable Angina: Is it time for a Requiem” Circulation. 2013;127:2452-2457.
  • Wadhera, R. K., Sukul, D., Secemsky, E. A., Shen, C., Gurm, H. S., Boden, W. E., & Yeh, R. W. (2019). Temporal Trends in Unstable Angina Diagnosis Codes for Outpatient Percutaneous Coronary Interventions. JAMA internal medicine, 179(2), 259-261.
  • Cannon CP et al. “Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor Tirofiban.” N Engl J Med 2001; 344:1879-1887.
  • Amsterdam EA et al. “2014 AHA/ACC Guideline for the management of patients with non-st-elevation acute coronary syndromes” Circulation. 2014;130:e344-e426.
  • Granger CB et al. “Predictors of hospital mortality in the Global Registry of acute coronary events” Arch Intern Med. 2003;163:2345-53

 


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