Robert A. Harrington, MD: Hi. I'm Bob Harrington from Stanford University. Today I'm joined by two friends and colleagues to have a conversation about some of the clinical trials we've been seeing here at the TCT [Transcatheter Cardiovascular Therapeutics] meeting in Denver.
First is Wayne Batchelor. Wayne is a clinical associate professor of medicine at Florida State University College of Medicine in Tallahassee, Florida. Next to Wayne is Michelle O'Donoghue. Michelle is an assistant professor at Harvard Medical School and an investigator in the TIMI Study Group at Brigham & Women's Hospital. Michelle, Wayne, thanks for joining us.
Wayne B. Batchelor, MD: Thank you.
Michelle L. O'Donoghue, MD, MHS: Thank you.
Dr Harrington: We're here at the TCT meeting, and there have been some great trials presented over the past couple of days. The first one that we're going to talk about is CULPRIT-SHOCK.[1] I'll give you my initial reaction: This is practice-changing. Does anyone want to describe the trial?
Dr O'Donoghue: Sure. In terms of what we saw with CULPRIT-SHOCK, it was looking at the question for patients who come in with either a STEMI [ST-segment elevation myocardial infarction] or non-STEMI in the setting of cardiogenic shock, whether or not we should be treating the culprit lesion only or should we be considering multivessel revascularization for patients who have multivessel disease. The findings were quite surprising on a lot of levels. I think that there had been a move recently toward more complete revascularization, especially in the setting of STEMI patients in light of some recent studies that had suggested benefit.[2]
The pendulum has now swung in the other direction. Even though we thought that there might be benefit for a multivessel approach for patients with cardiogenic shock, we actually saw that there was a lower risk for death in patients who only had the culprit lesion treated.
Dr Harrington: It was really interesting. When I previously practiced in this domain, the teaching had been: Open the culprit, and if the patient's still unstable, think about opening the other vessels if there's disease in the other vessels. That's what a lot of us did, and in fact the guidelines suggested that. They said: culprit only, but if the patient remains unstable, go after the others. This study says maybe not.
Dr Batchelor: Yes, a number of prior studies in more stable patients suggested that perhaps revascularization of all lesions at the same time might show some signal toward benefit. This turned that upside down. I think the message to the interventionalist is: Keep it simple, support the patient, deal with the culprit vessel, then "get out of Dodge," so to speak. That's important; it's a very pragmatic study, it's very simple in its design, but very, very impactful in the way we practice.
Dr Harrington: I like the way you said it. It really was testing the strategy of just get in and get out versus doing what you can. Michelle, as a trialist, what do you think of the endpoint, mortality plus renal replacement therapy?
Dr O'Donoghue: I wasn't too surprised that there was benefit in regard to treating the culprit lesion only for reducing the risk for renal replacement therapy. It was interesting that the rates of renal replacement therapy were a little bit north of 10%. A substantial number of people with cardiogenic shock end up needing renal replacement therapy.
What I thought was quite intriguing is that when you look at the number of days spent in the intensive care unit (ICU) or number of days required to come off pressors, those numbers actually ended up being similar between both groups. I would have thought that the trend toward a lower need for renal replacement therapy in the culprit-only arm might have translated into shorter length of stay in the ICU.
Dr Harrington: It was interesting to hear that mechanical ventilation use was roughly the same and that days in the ICU were roughly the same [in the two study arms]. Wayne, as a practicing interventionalist, did it surprise you that the contrast difference was substantial between the two groups?
Dr Batchelor: It didn't surprise me. What was a little surprising is that there was really no signal toward differences in renal failure. Many of these patients have acute tubular necrosis and acute insult to the kidneys. I would've thought that in the group getting more contrast delivery, you would see a signal in renal function. I thought there would have been a bigger difference.
Dr Harrington: I love the endpoint, particularly as you think about what PCORI [Patient-Centered Outcomes Research Institute] is doing. We're really trying to get at what's important for the patient. Needing renal replacement therapy is something that's pretty important for patients, so I liked that they included it.
Let's look at the big picture. The mortality rate in cardiogenic shock is still really high, and over the years it's not changed much. The SHOCK trial, certainly, with just revascularization, does drop it, but really nothing else.
Dr Batchelor: We're having a hard time staying south of 40%-50% mortality with cardiogenic shock patients. Even with some major advances in support, left ventricular assist devices (Impella®, basically), we're still not seeing the landmark changes that we like to see in the mortality rate. It's amazing how little impact we've had.
Dr Harrington: Why do you think that is? My reading of the literature is that in the STEMI population, if you make it to the hospital, your mortality is low. If you make it to the hospital and you have cardiogenic shock, your mortality, as you said, is exceedingly high. Therefore, almost all of the mortality of STEMI, or the large majority of mortality, is concentrated in this really small group of people. Why do you think that is, Michelle?
Dr O'Donoghue: I'm glad that there has been a shift toward trying to conduct more randomized controlled trials in this particular setting. There's been a hesitation sometimes to randomize patients who are that sick. I'm hoping that with more randomized trials being conducted, we might be able to start making an impact over time.
You're right that it's a little discouraging on some level. I thought Judy Hochman did a nice job of calling that out in the editorial.[3]
Dr Harrington: The editorial was quite nice, yes. I agree.
Dr Batchelor: I think we have to recognize that these folks come to the cath lab with tremendous baggage. We're studying a very complex phenomenon. Patients who have shock obviously tend to be a little older, have worse left ventricular function, more kidney dysfunction; they have pulmonary edema and all sorts of other issues. When you're just treating the artery, and we're trying to look at mortality differences, we still have a lot of other factors that are impacting their outcome. We're going to need really good ICU care, really good support of kidney function, and general medical care after the procedure in order to impact those mortality rates.
Dr Harrington: Here's something that's always intrigued me. David Holmes wrote the paper on this from the original GUSTO study.[4] If you do a landmark type of analysis and look at 30 days—if you had cardiogenic shock and you survived to 30 days, and you compare that group with people who do not have cardiogenic shock and survive to 30 days, their outcome at 10 years is the same. All the action's upfront. It suggests to me—and Judy Hochman has talked about this for years—that there's something reversible about the shock state. If you can get people through, then they're going to survive. We're only getting about 60% of them through.
Dr O'Donoghue: It's tough.
Dr Harrington: What else did you learn from the trial? Anything that grabbed you, either from a trial conduct perspective or lessons learned?
Dr O'Donoghue: One thing that I'm still grappling with is why was there a higher risk for death in patients who had multivessel revascularization. It was intriguing that when you looked at the breakdown for causes of death, it seemed to be driven by brain injury deaths. They were also a large category of unknown deaths.
The brain injury piece surprised me the most. When you looked at stroke as an individual outcome, it looked like the rates were similar between groups. I think there's a lot more there to be learned.
Dr Harrington: Any insight, if you think about mechanism, about why that might be?
Dr O'Donoghue: People have been hypothesizing about the catheter manipulation, which does make intuitive sense. Of course, we're going to lean towards things that make intuitive sense, but there's more there to understand.
Dr Harrington: Wayne, I've heard Deepak Bhatt over the past few days talking about this. You made a great comment: You get in, you get out. But around 17%-18% in the culprit group went back for further revascularization. That makes some sense to me—get in and get out, and then if they're not doing well, maybe come back. It's a strategy.
Dr Batchelor: Exactly. This was testing a strategy, not necessarily a dictum of doing just one thing. You're actually treating the patient's immediate issues, supporting them at the same time. The vast majority of patients did not need to come back, but for the 1 in 5 or so who do need to come back, doing culprit-only revascularization and allowing them to declare themselves ends up being safer than doing too much upfront and biting off more than you can chew and swallow.
I thought this was a great trial. These are very sick patients; they're hard to enroll in clinical trials. I thought the European investigators did a wonderful job of testing a hypothesis that's really important in helping move us forward in this really difficult patient population.
Dr Harrington: I agree with all of that, and what Michelle said is really important—that we have our preconceived beliefs about what works. Balloon pumps is one of those issues; we all believed that it worked. This same research group in Germany led a lot of the testing of that strategy, showing that maybe that's not the case.[5] Your point is, let's get some enthusiasm going for testing other things.
Dr O'Donoghue: You were both just saying that there's a reason to go back to the lab if somebody's not doing well, but you'd almost say that the results of this study even call that into question. We didn't see any lowering of heart failure. We didn't see any lowering of MI with the multivessel approach. Is it really going to benefit the patient even for 2 days later to go back to the lab? I don't know.
Dr Harrington: The only thing I would say to that, Michelle, is that you've got to say that it was a strategy. You did the culprit and you had the option to go back, so you have to package them together. You're absolutely right, how you tease those out. Maybe in that 17% they didn't have to go back, but we don't know that; it was all part of the strategy.
Dr Batchelor: Another interesting clinical trial phenomenon is that it's unusual to have a clinical study where we can use mortality as something to power against. I'm not sure that that's a good thing for the patients, but the good news is that we should be able to do more cardiogenic shock trials with properly conducted experimental designs and be able to show trends in mortality, not through mega trials but through moderate-sized trials.
Dr Harrington: These trials are powered with a few hundred patients. We were involved years ago in the TRIUMPH trial with Judy [Hochman] on tilarginine in shock patients.[6] These are mortality trials of hundreds of patients, not tens of thousands of patients.
CULPRIT-SHOCK is a good trial—well conducted, interesting results, practice-changing results, and it asks some questions for the broader field. Is that a fair interpretation?
Dr O'Donoghue: Absolutely.
Dr Batchelor: Absolutely.
Dr Harrington: Michelle, Wayne, thanks for joining us here. Thank you for listening to us discuss the CULPRIT-SHOCK trial from the TCT meeting in Denver.
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Cite this: Revascularization in CS: Keep It Simple and Get Out of Dodge - Medscape - Nov 13, 2017.
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