ESC Interventional Cardiology Highlights
Keith A.A. Fox, MBChB, FRCP, FMedSci: Hello. I'm Keith Fox, and I'm here with Gregg Stone at the European Society of Cardiology. We've just come from a really interesting hotline session. Let's address the question of what's happening with the bioresorbable stents. Gregg, what are your insights?
Gregg W. Stone, MD: First, it's a pleasure to speak to you on this really interesting topic. Bioresorbable scaffolds have been designed, basically, to try to have the same mechanical support functions and drug elution capabilities of a metallic drug eluting stent within the first year but then completely resorb over the next 7 years.
Dr Fox: So that you go out to the endogenous relaxation.
Dr Stone: Right, so by getting rid of the stent, if you will, after the first few years, you get the native conformability of the vessel back. It gets cyclic pulsatility back, normal vasomotion. Nitric oxide is produced, which is good for vascular health. And then you can have normal vascular adaptive responses.
Dr Fox: Gregg, that all sounds terrific. But does it translate into patient benefit?
Dr Stone: Well, we've got to find out, and I think there's good rationale that it might happen. There's a series of randomized trials with this one particular scaffold, the Absorbâ„¢ everolimus-eluting bioresorbable scaffold (Abbott Vascular; Santa Clara, California). It's made out of a PLLA, a poly-l-lactide material. The goal of these studies is first to see if it's at least as good within the first year as a metallic drug-eluting stent, because they've gotten pretty good, and then to follow them for up to 5 years to see if the results actually become superior.
We’re just starting to see the 1-year data from these randomized trials. And as you mentioned, we saw two new studies today in the hotline session. The first was ABSORB Japan, and it was the pivotal regulatory approval trial for the Absorb scaffold in Japan. So 400 patients, a modest-sized randomized trial of Absorb vs Xience™ (Abbott Vascular, Santa Clara, California), both eluting everolimus, with Xience made out of cobalt chromium metal.
Dr Fox: And a pretty low-risk population.
Dr Stone: Very low-risk population, what we call workhorse lesions, simple noncomplex lesions. There were some subtle differences in the procedure; the Absorb procedure took a little bit longer. The acute results weren't quite as good in terms of acute gain. The diameter of stenosis was a little bit higher. But the 1-year outcomes were not inferior. They were very similar in terms of rates of target lesion failure, myocardial infarction, revascularization, and stent or scaffold thrombosis.
Dr Fox: It was about 1.5% scaffold thrombosis.
Dr Stone: Yes, which actually is a little bit high for an Asian population. They usually have lower rates than Western Europe or the United States. But for this size study, probably the most important was to look at the angiographic follow-up. This was the first study [on the Absorb scaffold] that reported routine angiographic follow-up in a year.
Dr Fox: And they had very high completion of the angiographic follow-up. It was impressive.
Dr Stone: It was a well-done, high-quality study. And when you looked at what really matters, which is what's called the in-segment measures—that's the device itself and the margins of the device—they were very similar between Absorb and between Xience. So this bodes well for the 1-year outcomes, although given the modest size of the study, we need much larger studies to be sure.
Dr Fox: One of the things you mentioned was how good the existing technology is. It's pretty hard to show benefit over that. Is this an elegant biological solution looking for a problem?
Dr Stone: That's a great question. In the first year, no one thinks these new devices will be better. But after 1 year, with all metallic stents, whether drug-eluting or bare metal, there is about a 2%-3% per year rate of problems arising from the stent site. That's because the stent cages the vessel, new tissue grows inside, and you get neoatherosclerosis, which is a new problem that we're starting to recognize. You can get late thrombosis or late restenosis. You can have late strut fractures, late polymer hypersensitivity reactions. And there's a variety of reasons for the 2%-3% of problems every year. Some of our patients will have these devices for 30, 40 years, so do the math.
Dr Fox: This is going to need long-term follow-up and also big numbers to demonstrate differences in outcome.
Dr Stone: And in that regard, we're enrolling right now the ABSORB IV trial, which is a total of 5000 randomized patients. At the upcoming Transcatheter Cardiovascular Therapeutics conference, we will report ABSORB III, which is 2000 randomized patients. And with ABSORB III and IV, we'll have the power to be able to demonstrate superiority from year 1 through year 5. But it's going to take us 7 years before we have those results.
Dr Fox: Important developments, but it's on the way rather than here yet.
Dr Stone: Exactly. Right now, we're focusing on 1 year because there have been more than 100,000 of these implanted in humans around the world. And people are using them because of the promise of what's to come. The very meticulous imaging studies show how different the long-term results appear to be. But the question is: Should we be using them now without long-term data, which are not coming for another 5-7 years?
Dr Fox: Now one of the other interesting studies presented was trying to tackle the question of fractional flow reserve (FFR), noninvasively by CT. What was your take on this study?
Dr Stone: Well, as an interventional cardiologist, we get frustrated when we take patients to the cath lab who have chest pain or atypical anginal-type syndrome, and we find normal coronary arteries. Wouldn't it be wonderful if we could avoid doing an invasive procedure on those patients? If I never cath another patient with normal coronary arteries in my life, it will be too soon.
Dr Fox: You won't be sad.
Dr Stone: I will not be sad. FFRCT is a way of using a noninvasive test (CT angiography) that is reasonably good at showing us anatomy. But as we know, anatomy is not the same as physiology, and a lot of patients will have 30%, 40%, 50% plaque, which is not hemodynamically significant. It does not cause angina. FFRCT is a way to use quantitative computerized hemodynamic modeling to look at the severity of stenosis, at the amount of myocardial mass that the lesions subtends, taking in a length and volumetric measures. Then, they are able to come up with a fractional flow reserve measurement, which is actually what we measure with FFR in the cath lab. It's a difference in pressure when we stimulate hyperemia. And they're able to duplicate this quite closely using this noninvasive test.
Dr Fox: But it's not instant. It takes a while to process.
Dr Stone: Currently, it takes a supercomputer to be able to do these computational analyses. The dataset from a CT is sent to the particular company that has developed this algorithm named HeartFlow. The result comes back within a half day or a day. In the future, this will be done very quickly, possibly through the cloud.
Dr Fox: One of the take-home messages from this for a population with an intermediate pretest was that they could rule out caths in about 61%?
Dr Stone: This was a nonrandomized study. They took two large sequential cohorts who had an intermediate probability and some sort of chest pain syndrome, so they were going to get cathed. The first group underwent cardiac catheterization, and in the second group they did FFRCT. If the FFRCT was negative, then they avoided cath. The primary endpoint was the percentage of patients who did not have obstructive disease. In other words, we avoided sending them unnecessarily to the cath lab.
In approximately 70%, they were able to avoid going to the cath lab. The percentage of obstructive disease they found with revascularization was very similar. They only have 6-month outcomes to date. There were very few events in either group. In this nonrandomized study, they were able to avoid sending a lot of patients to the cath lab who did not appear to have physiologically significant coronary disease by this FFRCT test, saving a lot of money.
Dr Fox: And importantly, there wasn't an excess of radiation exposure.
Dr Stone: Exactly, so all of the patients are getting an FFRCT, but there was no significant difference in the amount of radiation exposure.
Dr Fox: Great. And finally, can we just touch on the part of MATRIX that was presented?
Dr Stone: MATRIX is a tremendous investigator-sponsored randomized trial that had actually three separate levels of randomization. They had about 8400 patients with acute coronary syndromes who were randomized to radial vs femoral access. They had about 7600 who were undergoing percutaneous coronary intervention (PCI) who were randomized to bivalirudin vs heparin. And then, of the bivalirudin patients, they had about 3600 who were randomized to either get no infusion after PCI or to get a post-PCI infusion. And they had previously reported those first two limbs.
They found that there was less bleeding with radial vs femoral but no overall difference in ischemic outcomes. They found that bivalirudin reduced mortality and bleeding compared with the heparin arm. But now they were asking if we can fine-tune the bivalirudin because there is a small increase in acute stent thrombosis with bivalirudin. It seems like the bleeding benefit overwhelms that, but wouldn't it be nice to overcome that? So they randomized patients to either no post-PCI infusion or a post-PCI infusion.
Dr Fox: This was a 4-hour infusion, wasn't it?
Dr Stone: Yes, but it gets a little tricky because they started out using a low-dose infusion.
Dr Fox: And they switched during the course of the study.
Dr Stone: Right. During the study, data from other studies started to come out to suggest that in a nonrandomized fashion, the low dose didn't seem to be doing anything, but continuing the PCI dose at 1.75 mg/kg/hour seemed to prevent any risk for acute stent thrombosis without causing more bleeding. So they told the sites that their recommendation is to switch to the high dose. So they had two totally different doses in the infusion arm, and what they found was that, overall, there was a nonsignificant trend towards a benefit with the infusion. But it was nonsignificant. When they looked at this nonrandomized comparison of the low-dose infusion vs the high-dose infusion, they found what everyone else has been finding, and that is that the high-dose infusion basically abolished any risk for stent thrombosis and did not increase bleeding. In fact, mortality was lower in that group.
Dr Fox: Yeah, so that's really an important take-home message.
Dr Stone: It really is. It suggests that if you use bivalirudin appropriately in patients with acute coronary syndrome, you can reduce major bleeding, reduce mortality, have similar ischemic protection, and prevent any risk for stent thrombosis. Now it takes a 4-hour post-PCI infusion, and there is some increased cost with bivalirudin compared with heparin, although now that it's generic or off-patent in both Europe and the United States, the price is starting to radically decline.
Dr Fox: The price is going to go down. So Gregg, this was a really interesting session. We're very grateful to you for these insights because I think that here are some studies that a lot of people are going to be interested in.
Dr Stone: My pleasure.
Dr Fox: Thank you for listening, here from the European Society of Cardiology.
Bioresorbable Stents
Keith A.A. Fox, MBChB, FRCP, FMedSci: Hello. I'm Keith Fox, and I'm here with Gregg Stone at the European Society of Cardiology. We've just come from a really interesting hotline session. Let's address the question of what's happening with the bioresorbable stents. Gregg, what are your insights?
Gregg W. Stone, MD: First, it's a pleasure to speak to you on this really interesting topic. Bioresorbable scaffolds have been designed, basically, to try to have the same mechanical support functions and drug elution capabilities of a metallic drug eluting stent within the first year but then completely resorb over the next 7 years.
Dr Fox: So that you go out to the endogenous relaxation.
Dr Stone: Right, so by getting rid of the stent, if you will, after the first few years, you get the native conformability of the vessel back. It gets cyclic pulsatility back, normal vasomotion. Nitric oxide is produced, which is good for vascular health. And then you can have normal vascular adaptive responses.
Dr Fox: Gregg, that all sounds terrific. But does it translate into patient benefit?
Dr Stone: Well, we've got to find out, and I think there's good rationale that it might happen. There's a series of randomized trials with this one particular scaffold, the Absorbâ„¢ everolimus-eluting bioresorbable scaffold (Abbott Vascular; Santa Clara, California). It's made out of a PLLA, a poly-l-lactide material. The goal of these studies is first to see if it's at least as good within the first year as a metallic drug-eluting stent, because they've gotten pretty good, and then to follow them for up to 5 years to see if the results actually become superior.
We’re just starting to see the 1-year data from these randomized trials. And as you mentioned, we saw two new studies today in the hotline session. The first was ABSORB Japan, and it was the pivotal regulatory approval trial for the Absorb scaffold in Japan. So 400 patients, a modest-sized randomized trial of Absorb vs Xience™ (Abbott Vascular, Santa Clara, California), both eluting everolimus, with Xience made out of cobalt chromium metal.
Dr Fox: And a pretty low-risk population.
Dr Stone: Very low-risk population, what we call workhorse lesions, simple noncomplex lesions. There were some subtle differences in the procedure; the Absorb procedure took a little bit longer. The acute results weren't quite as good in terms of acute gain. The diameter of stenosis was a little bit higher. But the 1-year outcomes were not inferior. They were very similar in terms of rates of target lesion failure, myocardial infarction, revascularization, and stent or scaffold thrombosis.
Dr Fox: It was about 1.5% scaffold thrombosis.
Dr Stone: Yes, which actually is a little bit high for an Asian population. They usually have lower rates than Western Europe or the United States. But for this size study, probably the most important was to look at the angiographic follow-up. This was the first study [on the Absorb scaffold] that reported routine angiographic follow-up in a year.
Dr Fox: And they had very high completion of the angiographic follow-up. It was impressive.
Dr Stone: It was a well-done, high-quality study. And when you looked at what really matters, which is what's called the in-segment measures—that's the device itself and the margins of the device—they were very similar between Absorb and between Xience. So this bodes well for the 1-year outcomes, although given the modest size of the study, we need much larger studies to be sure.
Dr Fox: One of the things you mentioned was how good the existing technology is. It's pretty hard to show benefit over that. Is this an elegant biological solution looking for a problem?
Dr Stone: That's a great question. In the first year, no one thinks these new devices will be better. But after 1 year, with all metallic stents, whether drug-eluting or bare metal, there is about a 2%-3% per year rate of problems arising from the stent site. That's because the stent cages the vessel, new tissue grows inside, and you get neoatherosclerosis, which is a new problem that we're starting to recognize. You can get late thrombosis or late restenosis. You can have late strut fractures, late polymer hypersensitivity reactions. And there's a variety of reasons for the 2%-3% of problems every year. Some of our patients will have these devices for 30, 40 years, so do the math.
Dr Fox: This is going to need long-term follow-up and also big numbers to demonstrate differences in outcome.
Dr Stone: And in that regard, we're enrolling right now the ABSORB IV trial, which is a total of 5000 randomized patients. At the upcoming Transcatheter Cardiovascular Therapeutics conference, we will report ABSORB III, which is 2000 randomized patients. And with ABSORB III and IV, we'll have the power to be able to demonstrate superiority from year 1 through year 5. But it's going to take us 7 years before we have those results.
Dr Fox: Important developments, but it's on the way rather than here yet.
Dr Stone: Exactly. Right now, we're focusing on 1 year because there have been more than 100,000 of these implanted in humans around the world. And people are using them because of the promise of what's to come. The very meticulous imaging studies show how different the long-term results appear to be. But the question is: Should we be using them now without long-term data, which are not coming for another 5-7 years?
Dr Fox: Now one of the other interesting studies presented was trying to tackle the question of fractional flow reserve (FFR), noninvasively by CT. What was your take on this study?
Dr Stone: Well, as an interventional cardiologist, we get frustrated when we take patients to the cath lab who have chest pain or atypical anginal-type syndrome, and we find normal coronary arteries. Wouldn't it be wonderful if we could avoid doing an invasive procedure on those patients? If I never cath another patient with normal coronary arteries in my life, it will be too soon.
Dr Fox: You won't be sad.
Dr Stone: I will not be sad. FFRCT is a way of using a noninvasive test (CT angiography) that is reasonably good at showing us anatomy. But as we know, anatomy is not the same as physiology, and a lot of patients will have 30%, 40%, 50% plaque, which is not hemodynamically significant. It does not cause angina. FFRCT is a way to use quantitative computerized hemodynamic modeling to look at the severity of stenosis, at the amount of myocardial mass that the lesions subtends, taking in a length and volumetric measures. Then, they are able to come up with a fractional flow reserve measurement, which is actually what we measure with FFR in the cath lab. It's a difference in pressure when we stimulate hyperemia. And they're able to duplicate this quite closely using this noninvasive test.
Dr Fox: But it's not instant. It takes a while to process.
Dr Stone: Currently, it takes a supercomputer to be able to do these computational analyses. The dataset from a CT is sent to the particular company that has developed this algorithm named HeartFlow. The result comes back within a half day or a day. In the future, this will be done very quickly, possibly through the cloud.
Dr Fox: One of the take-home messages from this for a population with an intermediate pretest was that they could rule out caths in about 61%?
Dr Stone: This was a nonrandomized study. They took two large sequential cohorts who had an intermediate probability and some sort of chest pain syndrome, so they were going to get cathed. The first group underwent cardiac catheterization, and in the second group they did FFRCT. If the FFRCT was negative, then they avoided cath. The primary endpoint was the percentage of patients who did not have obstructive disease. In other words, we avoided sending them unnecessarily to the cath lab.
In approximately 70%, they were able to avoid going to the cath lab. The percentage of obstructive disease they found with revascularization was very similar. They only have 6-month outcomes to date. There were very few events in either group. In this nonrandomized study, they were able to avoid sending a lot of patients to the cath lab who did not appear to have physiologically significant coronary disease by this FFRCT test, saving a lot of money.
Dr Fox: And importantly, there wasn't an excess of radiation exposure.
Dr Stone: Exactly, so all of the patients are getting an FFRCT, but there was no significant difference in the amount of radiation exposure.
Dr Fox: Great. And finally, can we just touch on the part of MATRIX that was presented?
Dr Stone: MATRIX is a tremendous investigator-sponsored randomized trial that had actually three separate levels of randomization. They had about 8400 patients with acute coronary syndromes who were randomized to radial vs femoral access. They had about 7600 who were undergoing percutaneous coronary intervention (PCI) who were randomized to bivalirudin vs heparin. And then, of the bivalirudin patients, they had about 3600 who were randomized to either get no infusion after PCI or to get a post-PCI infusion. And they had previously reported those first two limbs.
They found that there was less bleeding with radial vs femoral but no overall difference in ischemic outcomes. They found that bivalirudin reduced mortality and bleeding compared with the heparin arm. But now they were asking if we can fine-tune the bivalirudin because there is a small increase in acute stent thrombosis with bivalirudin. It seems like the bleeding benefit overwhelms that, but wouldn't it be nice to overcome that? So they randomized patients to either no post-PCI infusion or a post-PCI infusion.
Dr Fox: This was a 4-hour infusion, wasn't it?
Dr Stone: Yes, but it gets a little tricky because they started out using a low-dose infusion.
Dr Fox: And they switched during the course of the study.
Dr Stone: Right. During the study, data from other studies started to come out to suggest that in a nonrandomized fashion, the low dose didn't seem to be doing anything, but continuing the PCI dose at 1.75 mg/kg/hour seemed to prevent any risk for acute stent thrombosis without causing more bleeding. So they told the sites that their recommendation is to switch to the high dose. So they had two totally different doses in the infusion arm, and what they found was that, overall, there was a nonsignificant trend towards a benefit with the infusion. But it was nonsignificant. When they looked at this nonrandomized comparison of the low-dose infusion vs the high-dose infusion, they found what everyone else has been finding, and that is that the high-dose infusion basically abolished any risk for stent thrombosis and did not increase bleeding. In fact, mortality was lower in that group.
Dr Fox: Yeah, so that's really an important take-home message.
Dr Stone: It really is. It suggests that if you use bivalirudin appropriately in patients with acute coronary syndrome, you can reduce major bleeding, reduce mortality, have similar ischemic protection, and prevent any risk for stent thrombosis. Now it takes a 4-hour post-PCI infusion, and there is some increased cost with bivalirudin compared with heparin, although now that it's generic or off-patent in both Europe and the United States, the price is starting to radically decline.
Dr Fox: The price is going to go down. So Gregg, this was a really interesting session. We're very grateful to you for these insights because I think that here are some studies that a lot of people are going to be interested in.
Dr Stone: My pleasure.
Dr Fox: Thank you for listening, here from the European Society of Cardiology.
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