Talking Tall Rounds®: Diagnosis and Management of INOCA

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Khaled Ziada, MD:

Good morning, everybody. Just to stay on time, we're going to get started with the Tall Rounds today. I'm Khaled Ziada, I'm one of the interventional cardiologists for those who don't know me. The topic today is going to be diagnosis and management of ischemia with no obstructive coronary arteries or INOCA. We have a great set of talks to cover the topic from all its aspects. Just to not to take too much time, we're going to get started. Our first speaker is Tommy Das, one of our rising stars in interventional cardiology, and he's going to give us a couple of case presentations.

Thomas Das, MD:

So I'm just going to talk about a couple of cases to set the stage and get us started here. Our first case, this is a 71-year-old woman. She has a past medical history of the typical risk factors, diabetes, hypertension, sleep apnea, and she comes in as an outpatient reporting a few months of dyspnea on exertion, some sensation of chest burning with moderate activity. These symptoms have been bothering her, and so she gets the following workup. She has a nuclear stress test that shows no evidence of ischemia. She has an echo which is unremarkable, normal ejection fraction, no valvular disease. And given the nature of her symptoms and the persistence of her symptoms, she gets referred for a coronary angiogram, which you see the still frames of here. And importantly, really no evidence of any obstructive disease. Some mild non-obstructive stuff in the LAD, but otherwise no obstructive culprit disease that could explain her symptoms.

Contrast her case with case two. This is a 37-year-old woman, has a past medical history of hypertension, tobacco use and obesity, and she comes in more acutely. She has early onset, early morning chest pressure that wakes her from sleep and she presents to her local emergency room. She has a EKG that's done in the ER that shows a left bundle branch, which is unclear the timing on that if that's a new thing and the emergency room is concerned, this is her STEMI equivalent. They activate the lab, but in conversation with the team, her chest pain gets better. Her hemodynamics are stable. Her left bundle actually appears to be rate dependent more than anything. She's got negative enzymes, so she gets retriaged to the floor. And again, gets a pretty expansive workup. An echocardiogram that shows a normal ejection faction, no valvular disease, gets a coronary CT that shows some atherosclerosis but no obstructive lesions, even gets a PET scan with some concern for sarcoidosis, which has no evidence therein.

Has an exercise test that shows that that left bundle is rate dependent and comes on with activity and actually that test ends up being terminated due to fatigue and chest pain. So again, she goes for an angiogram, which again shows no evidence of obstructive disease. So while both these cases would probably have been conceptualized in the past as having non-cardiac chest pain, they didn't find any culprit on the angiogram. What we know now is that these patients have ischemia with no obstructive coronary artery disease there, INOCA. In 2018, the COVADIS group from Europe actually put together these following diagnostic criteria for INOCA. Essentially showing that patients would have symptoms suggestive ischemia, an absence of obstructive lesions, ideally shown on angiogram, evidence of ischemia with functional testing, and we're going to talk about some of the ways that that functional testing can happen, and then evidence of microvascular dysfunction that could be looked at invasively or noninvasively. And we're going to talk more about the different types of microvascular dysfunction here as we go on.

So two main endotypes of INOCA that we're going to focus on today, one is microvascular angina, essentially wherein there is disease, is a small vessels of the coronary tree, those that are smaller than the naked eye. And while those vessels may be small, they actually control most of the perfusion of the myocardium. We'll talk more about how that testing is done, but essentially, invasively or noninvasively, what we're looking for is a coronary flow reserve that's low and index and microvascular resistance that is high. And we'll talk more about MLR later too. But essentially that can be tested for invasively or noninvasively too.

We also have vasospastic angina as another endotype of microvascular, excuse me, of INOCA. This, there is no standardized noninvasive ways to test for, but invasively, what we do is actually is we can give a provocative agent such as intracoronary acetylcholine or intravenous ergonovine and look for evidence of spasm. We have both epicardial or macrovascular spasm where we actually see the lumen of the artery shrink by about over 90%. And we also have evidence of ischemia by EKG and reproduction of the symptoms. And you have microvascular spasm where you don't have that angiographic change in the vessel diameter, but you do have symptoms and you do have EKG changes.

So with that groundwork, we're going to go back to our two cases. Case one, this is a woman in her seventies who had typical symptoms but a negative angiogram. She goes to the lab, she has her negative angiogram, but then she goes for microvascular testing, and we'll talk more about this screen later, but essentially you'll see that her CFR is low, her coronary flow reserve is low, and her index of microvascular resistance is high. And so she ends up being diagnosed with coronary microvascular disease or microvascular angina is the cause of her symptoms.

Our second case, this is a younger woman who had acute onset chest pain in the morning. Her CFR is high, or normal, excuse me, and her IMR is also normal. So she doesn't have microvascular disease per se, but when we do provocative testing with acetylcholine on the left, you see her angiogram at bed rest and then on the right you see her angiogram after intracoronary acetylcholine. And you see that the lumen has spasmed essentially greater than 90%. And additionally, she has reproduction of her anginal symptoms and EKGs changes. So she gets diagnosed with vasospastic angina. So again, just two cases to set the stage and kind of show the different endotypes that we're talking about as well.

Stephen Ellis, MD:

Good morning, and thank you for coming. So the picture on the left is the way we in the cath lab looked at coronary arteries for years, but the picture on the right is a little more representative of actually coronary vessels and profusion, but we didn't look at that. Instead, we had many patients, typically women, who would come to us with chest discomfort. We saw nothing on the angiograms. We say, "Oh honey, I'm sorry, maybe it's in your head. Go see your psychiatrist." And unfortunately, that happened way too often. From an academic standpoint, the issue began to come to light with the NHLBI-funded WISE trial. Look at the date here. This was published over 20 years ago, but it's a really important study. So they measured coronary flow reserve using doppler, which was the only available technique at the time, and 159 patients with chest pain and no obstructive coronary disease. And 47% of these patients had subnormal coronary flow reserve, suggestive of microvascular dysfunction. Perhaps this overestimates the prevalence, but it gave us an idea that we were missing what I showed to you on the previous slide, on the right side.

What's the prevalence? This is really hard to know because you got to make the diagnosis. But to do that, you have to triage the patient to cath and then do appropriate in-lab testing. And still, in most centers in this country, we don't do that. So it may be as high as 40 to 50% of patients with chest pain.

Probably not quite that high, but it could be that high. And where does that data come from? Well, this is a report of over 3 million patients in the ACC-NCDR registry undergoing catheterization. In column one, which is right here. These are patients that had no stenosis greater than 20%. In column two are patients that had stenosis 20 to 50%. Now granted, there's no FFR from this data, so it's rough, but look at this, it could be as many as 60% of the patients that come to the cath lab have some other form of coronary artery disease.

More recently, the ischemia trial looked at this ischemia and attempted to roll over 8,500 patients. Those patients that had moderate or severe ischemia, they underwent CTA, and 13% of them were diagnosed with INOCA, most commonly women, younger women, and patients with less severe ischemia. One of the problems with this topic is this is a heterogeneous group of patients. Sometimes it's secondary to a variety of things, CKD, morbid obesity, HFpEF, and it's been very hard to sort out treatments that are effective. The basic cath lab testing has already been briefly described by Tommy. We have three basic measures. We can measure FFR and the epicardial coronaries by placing a wire down the coronaries and then measuring the pressure after the administration of adenosine.

And that's the standard test. But this ignores the pre-arterials, the arterials and the capillaries, the latter three being evaluated by IMR, and then CFR is somewhat more all-encompassing. It addresses the coronary vessels in all of these areas. There is emerging data looking at the predictive capability of CFR and IMR in particular. And so if you look over here to get started, patients with an abnormal CFR are below this line here, and those with an abnormal IMR are to the right of this line here. So the double negatives or double positives are here, and they have the worst prognosis. The next worst prognosis appears to be in this group, which has an abnormal CFR, but a normal IMR.

What about treatment? Oh, this is woefully understudied. There are many, usually non-randomized studies and no consistent benefit. This is from a relatively recent study, and the breakdown is as follows, I'll invite you to look predominantly at the non-hatched lines here. So these are placebo controlled trials here. So we have all of three placebo controlled trials looking at ACEs and ARBs. One showed effect, two did not show effect, statins, three trials, no effect more commonly, and we go across the board. There's no real consensus or solid basis for treatment of many of these patients, maybe with the exception of bridges or spasm. But in terms of microvascular disease, we just don't have much data that's good.

There are better studies to come. I'll just mention one and then I'll step down. We are finally going to get some decent-sized studies in the near future. This is an overview of the WARRIOR trial, which will randomize 4,400 patients to atorvastatin RAS blockade or aspirin, essentially as a placebo. So there's going to be much more information coming down the line. I think in the next decade, we'll learn how to treat many of the subtypes of patients within this group, but I'll remind you, it's a heterogeneous group and it's been a challenge to study over the years. Thank you.

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