CardioNerds at SCAI SHOCK 2022: The ISO-Shock Trial

The Incorporating SuperSaturated Oxygen in Shock (ISO-Shock) study assessed the safety and efficacy of TherOx SuperSaturated Oxygen (SSO2) in patients with ST Elevation Myocardial Infarction (STEMI) and cardiogenic shock treated with mechanical circulatory support.

In this video interview, Drs. Carrie Mahurin (University of Vermont) and Zaid Safiullah (Johns Hopkins) of the CardioNerds spoke with Drs. Jesse Jorgensen (Prisma Health), and Nainesh Patel (Lehigh Valley Health Network) to discuss the clinical implications of the ISO-Shock Trial.

This interview was conducted as part of a collaboration between CardioNerds and SCAI SHOCK 2022, led by Dr. Julie Power, Dr. Dan Ambinder, and Dr. Amit Goyal with mentorship from Dr. Alex Truesdell.

Dr. Zaid Safiullah: So, my name is Zaid Safiullah. I’m one of the 2022 CardioNerds Academy Fellows. I’m a third-year internal medicine resident of the Johns Hopkins Hospital and I’m currently applying for cardiology fellowship. I’m interested in a career in cardiac critical care and basic science. I’m really happy to be with you all tonight.

Dr. Carrie Mahurin: And I’m Carrie Mahurin. I’m a second-year cardiology fellow at the University of Vermont and I am a FIT trialist working with the CardioNerds on the Paraglide HF trial with mentorship from our site PI, Dr. Van Buren. I am still figuring out what I want to do when I’m grown up, but I think general cardiology with focus in heart failure.5 Back home in Montana is where I’m headed.

Dr. Zaid Safiullah: Great. So, thank you so much Dr. Jorgensen, Dr. Patel, for being with us today and being able to discuss this amazing super novel trial. So, I guess we can start with just Dr. Jorgensen introduction. So, Dr. Jesse Jorgensen’s interventional cardiologist and clinical assistant professor of medicine at the University of South Carolina. He attended medical school at Vanderbilt University and completed his internal medicine training at Northwestern University. He then returned to the south to pursue his cardiology training at Emory before joining the faculty at USC. He has participated in several key interventional cardiology trials including COOL-ARREST and safe BCI. Dr. Jorgensen, thank you so much for being with us tonight.

Dr. Jesse Jorgensen: Yeah. Thanks for having me.

Dr. Carrie Mahurin: And our other expert is Dr. Nainesh Patel who is an interventional cardiologist at Lehigh Valley Health Institute. He attended medical school at Ross University and completed residency at Lehigh Valley Health Systems. Dr. Patel went on to complete his cardiology and interventional cardiology fellowship at Main Healthline System and he has participated in an array of cardiac trials, too many that I could personally count, but of including the AMIHOT III and the IC-HOT studies, which were groundbreaking trials in exploring the SuperSaturated Oxygen therapy in acute AMI. He’s also been involved in other trials exploring thrombectomy, CardioMEMS, Impella, and electrical disturbances post TAVR amongst several others that I don’t have time to mention, but happy to have you both here.

Dr. Nainesh Patel: Thank you for the invitation.

Dr. Zaid Safiullah: So, Dr. Patel, maybe we could start with you. So, this study seems super novel to me, investigating the intracoronary delivery of SuperSaturated Oxygen and its effect on mortality. I was wondering if you could tell us more about the background and maybe some of the path to physiology that motivated this study.

Dr. Nainesh Patel: So, I think if we probably have to go back about 20 years to figure out what was the motivation for this trial. And the initial trials were done with SuperSaturated Oxygen to reduce infarct size. And I guess the first one was a 29-patient feasibility trial that was done early on, probably in the late 1990s. And that again showed that it was safe and feasible and that led to actually the AMIHOT one trial, which I was lucky to be part of as a fellow. And in the AMIHOT one trial, we looked at patients who came in with acute anterior infarct within 24 hours and who underwent PCI versus PCI plus SuperSaturated Oxygen. So, there were about 289 patients enrolled. There were I think 20 runs in patients and 269 patients that were randomized to the therapy versus a control arm. And we looked at reduction in infarct size.

Dr. Nainesh Patel: That’s what the primary endpoints we’re looking at. Reduction infarct size, reduction in ischemic burden, and improvement in LV contractility for a subgroup of anterior infarcts. And in that trial there was no statistical significant for patients who presented within 24 hours. There was 2% absolute risk reduction for the less than six hours and anterior STEMI there was a significant reduction. I think it was a 14% absolute risk reduction in infarct size. So, this led us to target the population, sort of a focus population. So, let’s look at now the anterior infarct and patients who present within six hours. So that led to the AMIHOT II trial. And the AMIHOT II trial, again, anterior MIs within six hours of presentation. There were 317 patients enrolled in that trial and there were 13 run-ins and 301 randomized to control versus PCI plus SSO two.

Dr. Nainesh Patel: Again, the AMIHOT II trial demonstrated that the SuperSaturated Oxygen administered following PCI with stenting significantly reduced infarct size with no statistically significant difference in 30-day mace. The FDA asked for some additional safety data because they recognized there was a couple of patients that had stent thrombosis. So, if you recall how this study was sort of designed was the catheter was indwelling. So, it was in the coronary where you did the PCI, you put a microcatheter right at the site of the stent and then infuse SuperSaturated Oxygen. So, they think that that might have been sort of the impetus for thrombus formation and couple of stent thrombus that may have occurred. Although there was no statistically significant difference, they sort of saw a sign that there was no safety. So, they asked for a second trial. After AMIHOT II was done, they said, “Well we need to see if there’s a better way to deliver the SuperSaturated Oxygen and can we do this with the catheter not in the vessel? Maybe at the left main.”

Dr. Nainesh Patel: So TherOx went back to the drawing board, created a special catheter that can deliver SuperSaturated Oxygen at high pressures through A what we call it. It was actually a diagnostic catheter, not a guiding catheter, but it was able to tolerate the high pressures. So back to drawing board, now a small substudy was done and I believe there’s 20 some patients that was studied in this safety and feasibility of the catheter place in the left main delivering oxygen. So that little trial was just done to look at the safety and again, prove that there was safety and efficacy of delivering the SuperSaturated Oxygen without having any thrombosis formation, which led the FDA to ask for more information.

Dr. Nainesh Patel: So, then they did the IC-HOT study. And in the IC-HOT study was actually just a registry. So, we were part of that registry. And in the registry we enrolled all those patients with acute anterior infarcts, Supersaturated Oxygen, but this time the catheter was left in the left main delivering oxygen to the whole left coronary. And again, because it was not an indwelling catheter, there was no stent thrombosis seen in this trial. The IC-HOT study actually showed that there was safe and feasible as well as there were no complications, there was no mortality within the 100 patients that were treated. So that led to, I think now looking at TherOx, it’s the ISO Shock pilot and feasibility trial. I don’t know if you want me to go into those details, but I think that’s what led to this whole trial of 60 patients being study in this trial. And again, looking at just safety and feasibility that we can do this now in cardiogenic shock patients.

Dr. Zaid Safiullah: No. That’s great. Thank you so much. Yeah. It’s great to learn how it made its way into therapy, but at the same time that this is an efficacious and safe therapy to deliver. I was wondering maybe if you could just speak more briefly about the path to physiology and why delivery of Super Oxygen to the site of a PCI or a stent has improved outcomes or what it does on the coronary level.

Dr. Nainesh Patel: So, I think SuperSaturated Oxygen as we’re looking at infarcted zone of myocardium and if you’re delivering oxygen to an ischemic zone, that there’s potential improvement by, I’m not sure if anybody knows real physiology of it. What’s the word? At least if you supply enough oxygen to that area, do you reduce the infarct size? And so, I don’t know if we really know the actual physiology of how it works, but I think just supplying oxygen to that area where there is lack of oxygen will help improve myocardial function.

Dr. Zaid Safiullah: Great. Thank you. Thank you so much.

Dr. Carrie Mahurin: So, sort of piggybacking off that Dr. Jorgensen, the delivery of this system, the SuperSaturated Oxygen system, is pretty cutting edge at least to my knowledge. It sounds like there’s more history, but could you share the logistics of delivering this via catheter and if there are safety concerns that you’ve encountered with the catheter engaged now in the left main system? We know that there’s a little safety concern specifically with probably LED, but what about left main for an hour?

Dr. Jesse Jorgensen: Sure. So, the protocol for the ISO shock trial involves a 60 minute. The product was set up for these patients to be treated in the treatment arm, so it’s randomized to either Impella plus PCI setting of STEMI shock versus Impella plus PCI plus SSO two. So, 30 patients get SSO two, 30 patients get Impella plus PCI without SSO two. So, for the treatment arm it’s a 60-minute infusion with a catheter sitting in the left main. I think with careful attention to catheter positioning and patient movement that this can be done safely. There’s obvious safety concerns if there’s an unstable patient by the nature of this study that’s moving or that potentially could deep seat the catheter. So, I think it’s a little bit different for us to leave a catheter in for that long without doing anything, but I think if people are mindful of patient positioning and movement that it could be done safely. So, I don’t have any huge concerns about it.

Dr. Carrie Mahurin: Okay. Thank you. And you think this is a pretty reproducible study at other centers? Or technique I should say.

Dr. Jesse Jorgensen: Yeah. I think the nice thing about the kind of concept behind the study is that the centers that are going to be participating I think are comfortable with the concept that arose out of the National Cardiogenic Shock Initiative, which is unloading the patient first with Impella, then proceeding with PCI, having a Swan-Ganz catheter in place, doing all of that and having a successful procedure. So now the patient’s revasterized, the infarct related vessel is open, the Impella is running, the Swan is in place, and all that’s left to do for the SSO two infusion is to place a standard shaped diagnostic catheter in the left main. I think the hardest part for us is going to be waiting that 60 minutes. So, I do think it’s reproducible for the type of center that’s going to be participating.

Dr. Carrie Mahurin: Makes sense. Thank you.

Dr. Zaid Safiullah: Great. So, follow-up question to that. So, when reading through the study protocol, it seems like the inclusion and exclusion criteria are very specific and actually quite extensive. So as a developing group of clinical trialists, I was wondering if you could share with us the thought process and motivations behind coming up with your inclusion and exclusion criteria.

Dr. Jesse Jorgensen: Yeah. So, I’m not going to take credit for coming up with the inclusion and exclusion criteria because I didn’t do that. That was set by the steering committee and the National PIs, but I think the rationale for having somewhat of a standard strict inclusion exclusion set of criteria is for this patient population you want to standardize the patients who are getting enrolled as much as possible. So, when you think about patients coming in with STEMI, shock, there are a lot of variables that can play into that. So, when you’re comparing outcomes, whether it’s infarct size by MRI or 30-day mortality or some of these things that we are wanting to look at, you want the patients and the two arms as homogeneous as possible.

Dr. Jesse Jorgensen: It’s not possible to make that completely equal, but the idea behind limiting enrollment to patients with left-sided infarcts, and really we’re thinking about LAD related STEMIs. So anterior STEMIs involving the LAD less than six hours from symptom onset. So, you want those early presenters or relatively early presenters who we are going to treat in the standard fashion of coming to the cath lab for primary reperfusion. I think excluding people who are 12 hours in or 18 hours into their infarct helps keep those treatment arms equal. So, I think that’s the main rationale for having a pretty strict inclusion exclusion protocol.

Dr. Zaid Safiullah: Great. Thank you so much.

Dr. Carrie Mahurin: So, Dr. Patel, we learned, and you sort of spoke to this earlier about the AMIHOT trial and that there was actually a trend towards hemorrhagic complications in a SuperSaturated Oxygen group. In the ISO shock group, there is an added bleeding risk of Impella now that we’ve added. And knowing this and understanding that the guidelines support IV antiplatelet agents with only a two-way recommendation, what was the reasoning behind requiring the use of these IV antiplatelet agents in this trial?

Dr. Nainesh Patel: I think we want to prevent stent thrombosis in these patients. Also, patients who come in with cardiogenic shock where they’re hyper perfusing. So, we know that the standard therapy that we’re using is not well absorbed. So, I think antiplatelet therapy, it’s probably better served than giving oral antiplatelet therapy. These patients are hyper perfusing, they’re sometimes obviously thrown up, and the antiplatelet therapy that they’ve received in the emergency department, they’ve maybe thrown up prior to even getting to the lab. So, you’re really not sure if they’re going to absorb it or not, and you know that you’re going to be leaving a catheter in place for 60 minutes. So, you have to make sure that these patients are anti-coagulated appropriately and that they’ve absorbed the either IV cangrelor or 2b3a, whichever way you choose to use. But those are the ones that are allowed to be used in this trial.

Dr. Nainesh Patel: So, I think it’s just basically absorption, make sure that that’s the problem, not the issue. And again, I think if the centers that are involved, as Dr. Jorgensen said, there are experienced centers who know how to place Impella. They know how to utilize single access if that’s the case and that’s the way you choose to do it. If you choose to do double access, you know can do it that way. But obviously these are centers that are experienced and making sure that patient get the right device with the right size and they’re taking care and being diligent about utilizing these devices in a safe manner.

Dr. Jesse Jorgensen: I think it’s controversial to some degree, this requirement in the protocol because I don’t think that most of us are using IV antiplatelet agents in our routine practice. I think most of us are loading on the table with either oral brilinta, oral effient as part of the usual standard of care. So I think this is a little bit different than what most people are accustomed to using in their daily practice, but I think the idea of IV antiplatelet agents is to ensure that every patient who’s enrolled in the trial, whether they’re randomized to SSO two therapy or the control arm, not getting SSO two therapy, everyone has consistent anticoagulation to help with the comparisons.

Dr. Carrie Mahurin: That makes a lot of sense.

Dr. Jesse Jorgensen: The question about bleeding with Impella with a 14 French sheath in place, plus A2B3 on board is a real concern. So, there’s clearly a tradeoff that we’ll have to manage and as all of us involved in the trial are accustomed to great care with access, getting access and then access like management is going to be key.

Dr. Zaid Safiullah: Great. So, thank you both so much for teaching us about the use of SSO two therapy and intracoronary, treating different lesions using this. We were wondering, I think we touched on this a bit earlier with Dr. Patel, but if you could just share if you have any kind of preliminary data that help motivate specifically these two arms of comparison or any kind of other findings that you all had seen personally that kind of made it, motivated you to better pursue the study.

Dr. Nainesh Patel: So, I think obviously AMIHOT one, when we saw a reduction in infarct size and improvement in wall motion, the contractility obviously helps us to think that if we can do something better than what we’ve had traditionally. So going back to 1996 I guess, Dr. Hoffman’s paper, PCI was our only therapy and for 20 plus years we’ve had nothing that’s improved our mortality in patients with cardiogenic shock. So finally, we’re seeing something with Impella usage where we’re seeing an improvement in mortality and now if we could sort of expand that to the cardiogenic shock patient, can we improve survival there?

Dr. Nainesh Patel: Now we participated in the NCSI Initiative and in my center I saw an improvement in survival. We went from 50% survival to 70% survival just using the shock protocol. So just educating everybody about the shock protocol really helped improve survive in our patients. Now we take that a step further with patients with cardiogenic shock, using the shock protocol and adding SSO two therapy, could we improve their LV function by just even a few percentages that maybe we may get less heart failure, maybe we may get less defibrillators put in? I think that’s sort of my thinking is that if we can improve the LV function a little bit over time period and improve survival just from NCSI, maybe this may help improve survival for the shock patients in the future.

Dr. Jesse Jorgensen: Yeah. So I would add to that, as far as motivation for participating, I think we also saw, after participating in the NCSI and seeing the data that Dr. O’Neal and his group presented with the progress that can be made by standardizing approaches to taking care of this patients, I think it made us realize that having a standardized approach can move the needle, but at the same time, we all still see these patients in clinical practice, the STEMI shock patients, who don’t always do well. And so, I think there’s a great deal of interest in new novel treatment modalities that can help improve things further. I don’t think we have any preliminary data to share from SSO two in STEMI shock because while the trial has started, as far as I know nationwide, we’re still yet to enroll the first patient. So, this is really new and fresh, and I think everyone’s eager to see how it goes.

Dr. Nainesh Patel: Just to add to that, remember that it’s almost difficult to do these studies in probably most institutions because these are shock patients. They’re having an infarct and to try to enroll somebody in that situation is always difficult. So you’re not always going to get thinking that next person that walks in with an anterior infarct and shock is the one that’s, “I’m going to be able to enroll,” because sometimes they’re unresponsive and if there’s no relative that’s available, you’re not going to be able to get an LAR, a legally authorized representative, to sign the consent form. This is probably why it’s hard to enroll these patients in clinical trials. And only those centers that have experience doing STEMI trials or shock trials are the only ones that are going to be able to enroll patients in this.

Dr. Zaid Safiullah: Sure. Yeah. Thank you so much. That sounds great.

Dr. Carrie Mahurin: We’re excited to see the results. We have a lack of everything for these kinds of patients. So, it’ll be exciting to see if there’s anything good that comes out of this. Thank you both Dr. Patel and Dr. Jorgensen for joining us tonight with the CardioNerds and the SCAI Shock 2022 collaboration. We really appreciate your input and your discussions. I thought it was really helpful and I also want to thank Dr. Alex Truesdale who’s the mentor for this program.