Did the ISCHEMIA Trial Change the Path to Cath in Stable Coronary Artery Disease?

Michelle L. O'Donoghue, MD, MPH; Rasha Al-Lamee, MBBS, MA, PhD; Jacqueline E. Tamis-Holland, MD


November 21, 2022

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. I'm Dr Michelle O'Donoghue reporting for Medscape. Joining me today are two interventional cardiologists with whom I've had the pleasure of speaking with in the past. We're doing a sequel, so to speak, to a prior conversation that we've had about the results of ISCHEMIA.

Joining me today are Dr Rasha Al-Lamee, from Imperial College in London, and Dr Jacqueline Tamis-Holland, from Mount Sinai in New York. Welcome, both of you. Thank you for joining us today.

To bring everyone up to speed, it's obviously been a rapidly evolving field, as we've had different trials along the way that have helped to build the evidence base that we now have. We've had COURAGE; Rasha, you've led the effort on ORBITA; and we've also had ISCHEMIA. We'll talk about where we are now, but Rasha would you remind everyone how the field has been set?

Studies on Revascularization in Stable Coronary Artery Disease

Rasha Al-Lamee, MBBS, MA, PhD: Thank you very much, Michelle. I think the stable coronary artery disease base has really changed over the last decade or two. It obviously started with COURAGE, which first shocked the world by telling us that in patients with stable coronary artery disease, we didn't need to rush them to revascularization, and that in fact, the outcomes for optimal medical therapy vs percutaneous coronary intervention (PCI) were much the same.

With ORBITA, we looked at symptomatic improvement and the difference between patients who had a placebo procedure vs PCI and didn't find the symptomatic improvement that we might have expected from PCI.

Now, with ISCHEMIA, we've really started to think about the patients who have a much higher burden of moderate or severe ischemia, and whether revascularization changes outcomes for those patients. Again, we're starting to see that the outcomes really aren't influenced by revascularization, be that PCI or coronary artery bypass graft (CABG).

I guess the final trial to really talk about is the REVIVED trial, which has told us that in patients with ischemic cardiomyopathy, the outcomes for patients who have PCI really aren't different from those who have optimal medical therapy.

There is a burden of evidence now that's driving us toward thinking that, at the very least, we have been in clinical equipoise between revascularization and medical therapy, but potentially, there's more to come to tell us exactly which patients in which revascularization may make an influence.

O'Donoghue: I think they know each time we've tried to dial up the level of risk, so to speak. With ISCHEMIA, really identifying those who have more concerning signs of ischemia on imaging or thinking about coronary CT angiography (CCTA) as a gateway for decision making. Yet, we still haven't been able to really modify concrete events.

We're not seeing a clear reduction in mortality or myocardial infarction (MI), but we are able to see symptomatic improvement. I think that many interventional have still said, "Well, for my patient who is having symptomatic stable angina despite maximal medical therapy, revascularization still may play a role in that setting."

Where do the guidelines currently put us in terms of how we manage our patients with stable angina?

Jacqueline E. Tamis-Holland, MD: Just like you said, we want to focus on symptom improvement, or whether we're going to change somebody's prognosis. Despite the ORBITA trial, there are many other studies that show that revascularization does improve symptoms, and so certainly, I think we all, as interventional cardiologists, reserve this is one of the most important reasons why we might revascularize somebody. In my opinion, it's really boils down to whether it's classic, typical angina or whether they're morbidly obese and have a little bit of dyspnea walking eight blocks, which may not be angina at all but may be chronic obstructive pulmonary disease (COPD). I think you have to tease out truly how symptomatic they are.

The other flip side of the guidelines is the recommendation for revascularization just to improve cardiovascular outcomes. Although PCI doesn't really have a role in terms of in terms of patients with stable disease and normal ejection fraction besides improving symptoms, I think that there's still some debate. Now, we have a class 2A recommendation, in part based on ISCHEMIA, to say that if you have somebody with multivessel disease, revascularization with either PCI or CABG can reduce your risk for cardiovascular events, including spontaneous MI and cardiovascular death.

Stress Testing and Fractional Flow Reserve (FFR)

O'Donoghue: How should we think about approaching our patient with stable angina for evaluation? Some people are still in the camp that it makes more sense to do a stress test or some sort of more functional assessment. Then, for other people, it's more of an anatomic assessment. Should we think about a CCTA is that kind of gateway before thinking about bringing somebody to the cath lab? Others may also still just bring them straight to the cath lab.

Where do you settle on that?

Al-Lamee: In the UK, it's been quite different for a long time. Since 2016, CT coronary angiography (CTCA) really has become the gateway for our patients with stable coronary artery disease. I think, increasingly, across the world that's also changed, and CTCA is becoming the flavor of what people do. Mainly, I use CTCA to exclude high burdens of anatomic risk — left main disease, very severe three-vessel disease — and to take out those patients with unobstructed coronary arteries.

What we've seen from a wealth of data is if we do a CTCA upfront, we not only characterize their risk, and of course, that really changes our preventive therapies but also reduces the number of patients that get to an invasive cath and have unobstructed coronary arteries. Clearly, there was a reduction in terms of costs for the system overall, but also risks that we put our patients through in terms of what happens next. For me, actually, the functional space has been reduced in my practice, and I use functional testing far less than I did in the past.

O'Donoghue: That's interesting. Jacqueline, what are your thoughts? Some would say that makes perfect sense as an approach. Then there are others who feel like, well, if I then see a 70% lesion when I bring that patient to the cath lab, how do I know if it's clinically relevant? Is that where you think about FFR or other ways of guiding your decision?

Tamis-Holland: I think it depends on what my question is about the patient. My question is, are your symptoms related to ischemia, ie, related to cardiac problems, then I do want a functional test of some sort. Sometimes CCTA with FFR is fine or instantaneous wave-free ratio (iFR) in the cath lab. If I just want to know if this is at all coronary artery disease, then it's easy because you do the cath and the CTA, and it's either negative or positive.

The flip side of it is, in terms of using it as a gatekeeper to cath after we've done the stress test, so not as an initial strategy but after we've done the stress test, like it was used in the ISCHEMIA trial. I also think it depends on the underlying patient's syndrome. If I see multivessel disease, they're going to have an indication for revascularization anyway, then why do the CTA because if it shows something that we pretty much think there's an indication for, we're going to go ahead and we're going to do something anyway, whether it's PCI or CABG.

In our country, I don't think any surgeon would do CABG without seeing a cath as opposed to CCTA. On the other hand, if it's a situation where their symptoms are not very strong, they happen to have ischemia because of a preoperative stress test prior to hernia surgery or something, then I think the CTA becomes very valuable.

I think it depends on the patient that I'm taking care of. I personally think why should we expose them to double the dye and double the radiation if we're going to go on to cath anyway?

O'Donoghue: With ISCHEMIA-EXTEND, it's interesting to see the results because we now have longer-term follow-up, and of course, with these types of studies, it's hard because there's crossover between the arms. It was interesting to see that, overall, even though the effect on all-cause mortality was neutral for an invasive approach, it was intriguing that there was a reduction in cardiovascular death and yet an uptick in noncardiovascular death. Unfortunately, we're not going to get more information beyond that by virtue of what data were being collected.

What are your thoughts there? Does this change your thinking at all or are you pretty much in the same place as before because there's no effect on mortality?

Al-Lamee: I find those results very interesting but quite confusing. I think what is interesting is to look at the trial design of that EXTEND subset. Beyond the initial follow-up of the ISCHEMIA trial, all events have now been adjudicated at the sites, and there isn't a clinical adjudication committee to really confirm the event adjudication. The ISCHEMIA investigators have told us that over 90% of events that were adjudicated by sites in the initial ISCHEMIA trial cohort had confirmed events by the clinical events committee, so things didn't really change.

Having said that, we know that there's always an issue with adjudications of cardiovascular death, and there can be real difficulties in trying to work out exactly what caused the death of the patient. We don't have any data on MI rates because of course that wasn't collected in that EXTEND subset. For me, those data are interesting and may be hypothesis generating, but I'm not sure what to make of it. I think, probably, we have to hang our hat on the all-cause mortality data where there really wasn't a difference.

Tamis-Holland: I do agree with you. I'm not sure what to make of those data.

I do think there was an interesting study that came out from ISCHEMIA 2 years back, where they looked at the CCTA results. When you had anatomy suitable for CABG or anatomy suitable for multivessel PCI, there was an improvement in the combined endpoint of cardiovascular death or MI. Again, it was only using CCTA patients and looking at those randomized to invasive vs conservative care.

I do think that there is a suggestion that perhaps cardiovascular death or MI is reduced in patients with a really severe burden of coronary artery disease, and so that's why I sometimes just go straight to the cath to understand what I'm doing. It is consistent with the findings that they saw in ISCHEMIA-EXTEND, but at least it supports the rationale that when you see severe coronary artery disease, greater than 70% with proximal LAD involvement, then maybe it implies a worse prognosis.

O'Donoghue: Who do we not think about doing testing in before bringing them to the cath lab? For instance, just practically, for somebody who comes in who's had a prior history of revascularization, let's say, are you still doing CCTA in those situations, or bringing them straight to the cath lab?

Al-Lamee: Our CTs aren't fantastic when there's artifact due to previous stents. Obviously, in the older population, so over the age of 70 years, we see very high calcium burdens and often our CTs are inconclusive. There's definitely a subset of patients where I think it's not as important.

I think Jacqueline has also mentioned that space where you're looking for a reduction in blood supply to the heart, but that may not be due to epicardial coronary disease. In women or people who have angina, and we're trying to find a cause, in those patients, maybe the CCTA isn't as valuable. There's definitely a subset where I think functional testing is still very important.

Has Practice Changed?

O'Donoghue: As a final thought and question, how do you feel that the field has really evolved since, essentially, COURAGE was the real first game changer in this space and then followed by the studies we discussed? Do you feel like there's been a tangible shift in practice during that time?

Al-Lamee: For me, what's changed isn't necessarily the numbers of patients who have revascularization. That may have changed over time. What I expect will have changed is the pathway and the approach that we take to these patients. I think we rush less now. I hear all the time from colleagues that they feel like they have the time to uptitrate medications, to reconsider symptoms, and to have quite an informed conversation with patients about what's next. Maybe, what's changed is our pathway to the cath lab and we'll see if, in time, revascularization numbers themselves change.

Tamis-Holland: I agree with that. I also feel that there's a more thoughtful decision making before the cath to really home in on what you're here for, what your symptoms are, and what the ejection fraction is. There's a really thoughtful understanding of the benefits of revascularization, again, before we even get to the cath lab. There's not that rush, so you have the time to talk to the patient, to really optimize medical therapy, and if you need to go on to cath, that's fine. You might end up with revascularization, but it would be after you've had a thoughtful process to decide that there was an indication for revascularization,

O'Donoghue: I think that we always make the comment, almost in passing, about optimizing medical therapy, and yet, I think there are too many clinicians who are still jumping ahead without having first really taken that critical step.

Thank you so much for discussing this very interesting topic that continues to evolve.

Al-Lamee: Thank you.

Tamis-Holland: Thank you.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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