Dr. Harriette Van Spall:
I'm Harriette Van Spall, Associate Professor of Medicine and Cardiologist at McMaster University in Canada, and I'm absolutely thrilled to have with me Dr. Gregg Stone, Professor of Medicine and Director of Transcatheter Cardiovascular Therapeutics. Welcome Dr. Stone.
Dr. Gregg Stone:
Thank you, Harriette. It's great to be there.
Dr. Harriette Van Spall:
We are here to discuss your presentation at ACC 21 on the Association Between Complete Revascularization and Clinical Outcomes, which was an exploratory analysis of the ISCHEMIA trial. Congratulations on your presentation.
Dr. Gregg Stone:
Thank you.
Dr. Harriette Van Spall:
And I'm going to start off by asking you for the rationale for this analysis in the context of prior studies and primary findings of the ISCHEMIA trial.
Dr. Gregg Stone:
Sure. Well as you know, ISCHEMIA is the largest randomised trial to date of patients with stable coronary artery disease with either absent or mild symptoms who could be managed either with a conservative strategy or a invasive strategy. And by an invasive strategy, we mean perform cardiac catheterization and then either revascularize the coronary artery disease with either angioplasty with stenting or with bypass surgery as appropriate. By a conservative strategy we mean don't take the patient to the cath lab, try to treat the patient with just standard antiplatelet agents, statins, and anti-anginal drugs to control their, symptoms and reserve catheterization and invasive procedures for breakthrough symptoms or primary events like heart attacks.
Dr. Gregg Stone:
And the overall ISCHEMIA trial showed that at the end of about four to five years followup in about 5,200 randomised patients, there were no major differences in the heart events of death or myocardial infarction between the two groups. Patients with a lot of symptoms felt better after revascularization, where patients with no symptoms, there was no difference in the terms of quality of life. So depending on a patient's preferences, you could manage most of these patients with either an invasive or conservative approach, depending really on their level of symptoms. And of course, importantly, the ISCHEMIA trial results don't apply to patients with left main disease or heart failure or poor left ventricular function or acute coronary syndromes.
Dr. Gregg Stone:
But here's where it gets interesting, because the ISCHEMIA trial was performed in more than 350 worldwide sites. And of course, while doctors, both interventionalists and surgeons, usually strive to completely revascularize the coronary tree, we know that we're not always successful. And prior studies have shown that the extent of revascularization achieved might affect the long-term outcomes. And we can measure the extent of revascularization achieved either anatomically, that is, for example, every 50% or greater blockage, were you able to bypass it or put a stent into it. Or ischemically or functionally, and that is we would only want to treat the lesions that actually are of ischemic potential and are human and are hemodynamically flow limiting.
Dr. Gregg Stone:
And prior studies have suggested that outcomes would be better if you achieve either anatomic or functional, that is ischemic, complete revascularization. But all the prior trials were limited. Most of them did not use a sophisticated core lab analysis to really rigorously assess the completeness of revascularization. They didn't adjust for the predictors of complete revascularization. Obviously the more extensive the coronary disease, the less likely you are to get complete revascularization, et cetera. And there was never really a comparator arm to see how much complete revascularization could affect outcomes compared to, say, a conservative approach. So in the ISCHEMIA trial, we used both multi-variable and propensity score adjusted techniques, a lot of sophisticated analyses, to look at the rates of completeness of revascularization and the impact that would have had compared to the conservative approach.
Dr. Gregg Stone:
And we found that approximately 45% of the patients achieved complete anatomic revascularization. About 58% of the patients achieved complete ischemic revascularization. And the outcomes were in general better with complete revascularization than incomplete revascularization. And when you compared it to a conservative approach, and when you did all sorts of propensity score adjustments to make sure the baseline characteristics of all the patients were similar, if you safely were able to achieve anatomic complete revascularization, the overall outcomes of the invasive approach increased, improved. Whereas in the main trial, at the end of four years, there was about a 2.5% benefit. If you achieve complete anatomic revascularization that increased to about 3.5%. In contrast, achieving complete ischemic or functional revascularization, didn't make a major difference to the overall outcomes. So you can't just focus on the most severe lesions. The other lesions, which may not even be ISCHEMIA producing also seem to have an long-term impact on cardiovascular death and myocardial infarction, and revascularizing those lesions are important too.
Dr. Gregg Stone:
So the bottom line from our results, the data suggests, in this very robust study, it's not a randomised trial, so these conclusions are not definitive, but I do believe that the data strongly support, if you are going to do an invasive approach, if you can safely achieve complete anatomic revascularization, the outcomes will be better for the patient. Of course, we never know when we can safely achieve complete revascularization with certainty, but you can get a good sense. When you see one or two major large lesions that are short and focal, you're pretty sure you're going to be able to safely revascularize those lesions. In contrast, when you see long, diffuse disease in the arteries, then you may not be able to completely revascularize. So this is one more factor that should be considered when deciding between an invasive and a conservative approach in patients with chronic coronary syndromes.
Dr. Harriette Van Spall:
So just a couple of points of clarification. At the end of the followup period, there was no difference in all cause mortality between the invasive and conservative strategies in the overall trial, is that right.
Dr. Gregg Stone:
That's correct. Absolutely right.
Dr. Harriette Van Spall:
And the benefits of the invasive versus conservative strategy in ISCHEMIA on the primary outcome was more pronounced, as you say, in those receiving anatomic revascularization versus functional, complete revascularization. How did you assess functional complete revascularization? What was your definition for that?
Dr. Gregg Stone:
Yeah, so it's a great question. So we had a very specific and sophisticated core laboratory analysis that we had pre-specified and pre-published that we would use in this trial. And for anatomic complete revascularization was pretty easy. It's a 50% narrowing, 50% diameter stenosis in any vessel that was two millimetres and larger. For functional complete revascularization, we looked at all the different kinds of ischemic tests that were available, both FFR and IFR in the cath lab, which is very specific and localised to individual lesions, stress echos, stress nuclear, stress PET, stress MRI, et cetera. Or regular stress tests, and regular stress tests are not localising, so for each of those, we required a certain severity of diameter stenosis as well. And we're getting into the weeds a little bit here. But basically if, for example, the FFR or the IFR in the cath lab was abnormal, that's a very, very good test for the saying that lesion is ischemic, and we just required that the Legion had to be at least 30% stenotic.
Dr. Gregg Stone:
If we had, for example, a localising non-invasive test, then we said there had to be a 50% damage to stenosis. If it was a non-localising test, like a markedly positive treadmill test, then we said it had to be by quantitative coronary angiography at least 60% stenotic. And finally, if there was no ischemic test of very severe anatomic stenosis, a 70% or greater stenosis would qualify for an ischemic test. And then we would look at what happened after the procedure. We would identify all those lesions at baseline, and then in the PCI patients, of course, you would see the angiogram. So you would know whether all the lesions got treated or not.
Dr. Gregg Stone:
For the bypass surgery patients, we don't have a post-bypass angiogram, but we would have the operative report. So the core laboratory would look at the operative report and would see where all the distal anastomoses were of the bypass graphs. And they would consider whether or not there was blood flow going antegrade or retrograde and filling disease segments, and filling side branches, et cetera. So much more sophisticated analysis than in our belief has ever been done before. So that's basically how we did it.
Dr. Harriette Van Spall:
And then a final point of clarification. Within the invasive group, complete revascularization, as you say, was associated with benefit in the primary end points at four years. Would you say that some of this benefit was attenuated when you adjusted for baseline imbalances and covariates or time covariates?
Dr. Gregg Stone:
Right, so great question. So the answer is yes. We did two analyses. First we just looked at the outcomes just in the invasive arm, whether or not the patients in the invasive arm achieved complete or incomplete revascularization. And in an unadjusted analysis, the outcomes were about 40% reduced. The hazard was about 0.6 with complete anatomic revascularization, but in the adjusted analysis, the hazard was about 0.8. So it was somewhat attenuated. So we then took the adjusted analysis and compared that to the conservative group in this inverse probability weighting rebalancing of the patients, as if all the invasive group with a balanced set of characteristics would have achieved complete revascularization at time zero. And that's how we got the final answer. So the answer is yes, there was some attenuation certainly, because the same characteristics that lead to incomplete revascularization are also poor prognostic factors for both death and myocardial infarction, so you have to take all that into account. But even after doing that, we did see better results with complete revascularization.
Dr. Harriette Van Spall:
In a frequent test analysis, they weren't all statistically significant, but certainly strongly favoured the complete approach. So do you have a couple of take home points for the clinician and how we could make this exploratory analysis actionable the point of care? Or do you think we need to follow on with a randomised controlled trial?
Dr. Gregg Stone:
No, that's a great, great question. So I think that we can make some practical recommendations here. I think whether you anatomically screen patients with either a CT angiogram, which is what's recommended in ISCHEMIA if you don't go to the cath lab, or with the diagnostic invasive coronary angiogram, I do believe while it's impossible to always predict whether you're going to be able to safely get complete revascularization, I think surgeons and interventionalists, if they're honest to themselves, have a good idea going in what their likelihood is. And one of the problems in ISCHEMIA was that in multi-variable analysis complete revascularization was more likely to be achieved after surgery than after PCI stenting. And I think that for many of the patients with complex coronary disease, those patients whom you can't get complete revascularization, you should refer them to surgery rather than do an incomplete job with PCI.
Dr. Gregg Stone:
So I think the real take home message is that patients will have different thresholds for wanting an invasive or conservative approach, and we always have to really listen to the patient and understand their wishes. And there are many different factors that will go into that calculus in terms of their age and frailty and ability to accept risk, et cetera, really wanting to be asymptomatic very quickly versus trying a medical approach, et cetera. And one of those factors that should now be considered, I think is the ability to be... The likelihood of being able to achieve complete revascularization. You can tell the patient that if you think you've got a situation where we think there's a really good chance, we can completely anatomically revascularize the patient, that there's even more of a likelihood that their late outcomes might be better with an invasive approach.
Dr. Gregg Stone:
And it was really a reduction in both cardiovascular death and myocardial infarction, but not all cause mortality as you noticed. If on the other hand we're not confident that we can get complete revascularization, then that would push me a little bit more to say, "Look, I don't think that we're going to be able to improve your long-term outcomes, so why don't we try a conservative approach," and then withhold the best revascularization, partial or whatever, for real breakthrough symptoms.
Dr. Harriette Van Spall:
Right, and perhaps also keep the overall prognosis and projected survival in mind since some of these benefits are long-term benefits rather than upfront ones. Thank you so much for your time with us this morning. Congratulations on your presentation. I was so delighted to meet you and I wish you well, and I hope we get to connect again.
Dr. Gregg Stone:
Well thank you, Harriette. This is my pleasure. I have the same wishes. Thank you.