Experts Discuss Protect II Trial

Supported by MAQUET Cardiovascular

TRANSCRIPT

MORTON J. KERN, MD, FSCAI, FAHA, FACC: Hello, I’m Mort Kern, from the University of California Irvine, and I’m here with Richard Smalling from the University of Texas in Houston, and we’re going to talk about the PROTECT II study: the use of the Impella support device and the intraortic balloon pump for high-risk percutaneous coronary intervention. Before we do that, I’m going to have Richard introduce himself and tell us his current activities. Richard?

RICHARD W. SMALLING, MD, PhD, FACC, FSCAI: Mort, thanks for having me. I’m an interventional cardiologist. I am the director of interventional cardiology at the Memorial Hermann Heart and Vascular Institute and the University of Texas Medical School at Houston.

DR. KERN: Great and as we discussed, you were an investigating center in the PROTECT II trial and had a role in putting patients into this trial. Could you summarize for us what this trial was about and the major conclusions?

DR. SMALLING: Well, the idea about the PROTECT trial is that it would show that using the Impella device to support high-risk angioplasty was not inferior to utilizing the balloon pump for the same patient subset. That was sort of the main hypothesis. The entry criteria were a little bit loose. I think ejection fraction’s in the 30%–35% range. Supposedly last remaining vessel or left main disease or left-main plus three-vessel disease and low EF; so I think that was the screening for entry into the trial.

DR. KERN: And what were the major adverse cardiac event endpoints that you were looking for.

DR. SMALLING: Acute myocardial infarction, mortality, the usual cohort of things, bleeding, those were the main things. I wasn’t terribly involved — our center, Dr. Dinkdus was the PI and the main enrolling person.

DR. KERN: The results of the study were presented here today, in open forum here at the ACC. Can you give us a summary of the outcomes.

DR. SMALLING: I think it sort of depends on who you are and what you think. There’s a subset of people that were very enthusiastic about the outcomes. Unfortunately, they stopped the trial before they reached their target enrollment. They’d actually been instructed by their DSMB to stop it a little earlier because of futility. They also found, interestingly, that the patients that were randomized to … the Impella device, they tended to have a lot higher incidence of rotational arthrectomy; there was some question about why that was and so forth. The bottom line is, mortality was the same. Their endpoints really didn’t show that much difference. In subgroup analysis, they felt that they Impella may have had a little advantage over balloon pump. I don’t think everybody was convinced of that, however.

DR. KERN: So do you think this study would tip the interventionalist to move in one direction or the other for high-risk angioplasty?

DR. SMALLING: That’s an interesting concept, you know? One has to get to: What is really a high-risk angioplasty. I think you and I are both old enough to remember that back in the mid-’80s, we determined that high-risk angioplasty was a patient with an ejection fraction of 25% or less, with a jeopardy score over 6. Well, they didn’t actually even mention a jeopardy score with this trial, which was sort of surprising; you would think that that would have been an important thing. The EFs were a little higher. And, I guess, based on our prior experience with other support devices — like, for instance, CPS and then, later on, the Tandem Heart — there really was not an advantage of so-called more vigorous support systems. And so, the balloon pump served as well. Many people … opted for standby supported angioplasty, meaning you had the balloon pump, in the majority of cases, in the room, you had the balloon pump ready to drop if you needed it, but then you just went ahead and did your intervention. So that’s sort of where we are, state of the art, right now.

DR. KERN: So would you say that because the study was stopped prematurely, we would consider this negative study or an equivocal study?

DR. SMALLING: Yeah, they didn’t meet their endpoints, and so it has to be considered a negative study in most people’s view. I guess another consideration is, if you really needed support, would the Impella device be enough to support the circulation if somebody had, for instance, asystole during the intervention, or if for whatever reason, they totally lost pump function. The Impella supposedly can pump at two-and-a-half liters a minute, but it depends on loading conditions. And I think those of us that have looked carefully at what it can really do, I think it may get one liter a minute at most, maybe more.^1-6 But I think, for all intents and purposes, it doesn’t support at a very vigorous level. So I think personally, if I had someone I was really worried about, I would opt for something more substantial like, for instance, a Tandem Heart device.

DR. KERN: OK, well I think this is a really good summary of the study and the presentation this morning. Are there any final thoughts you might want to add for those of us who want to read the PROTECT II study when it comes out?

DR. SMALLING: I suppose those of us in this current economic environment who have to look at costs of doing procedures and hospital costs, we have to consider a $20,000, $25,000 device, is that really necessary to do something that we could often do without any support at all, or perhaps with a less costly device like a balloon pump. And so I think, at the end of the day, there’d have to be a lot more evidence to tip us in favor of investing in a very expensive device.

DR. KERN: That’s great advice. I want to thank you for your time and insights, I really appreciate getting the chance to talk with you. I hope this has been helpful.

DR. KERN: Hello, this is Mort Kern again, we’re here at the American College of Cardiology in New Orleans. I’m from the University of California, Irvine, and I’m here with Ron Waksman from Washington Hospital Center. Ron, I’m going to let you introduce yourself.

RON WAKSMAN, MD: That is correct. I’m Ron Waskman, from the Washington Hospital Center. I’m an interventional cardiologist and also associate director of the division of cardiology and in charge of the experimental angioplasty research at the Cardiovascular Research Institute...

DR. KERN: We’re going to talk for a few minutes about the PROTECT II study results that were presented here in their form. And Ron, I know you’ve been involved with following the work of the PROTECT II investigators. Were you a trial site for this study?

DR. WAKSMAN: No, actually, we were not, but we have a lot of interest in high-risk PCI and using devices to make this safe — mainly safe — and also effective. We were not investigators, but we did try to look, based on the inclusion/exclusion criteria, on our own accord with the balloon pump. Because, if you recall, this study actually was comparing balloon time to the Impella device for patients who are high-risk PCI. And the composite endpoint was very complicated. They added like probably nine variables there, which is unusual for a study design. … They basically estimated that the event rate on the balloon pump would be higher than what we thought it should be. So we looked at our own data, and we found out that the actual — if you go by the inclusion/exclusion criteria and their endpoints — the overall event rate in the balloon pump would be much lower than they predicted and built in their sample size. About two years ago we were actually called to do futility analysis, which was recently done, and this was presented now because the DSMB actually decided to hold this study.

DR. KERN: If I recall, the study had about 450 enrolled patients, 426 were enrolled, and the study was stopped early because they did not meet their endpoints, is that correct?

DR. WAKSMAN: So they did a futility analysis and the DSMB decided to stop the study, which is also odd — why would you stop the study unless there are safety issues? We don’t know the reason. It seems that they said that, by the sample size that they have been designed, they would not meet the endpoint. But if this is an important thing, why wouldn’t you enroll more patients to meet the endpoint? So we don’t know exactly what were all the considerations. We were told there were no safety issues, but the DSMB decided that the study is not going to meet the endpoint based on the number of patients that were supposed to be recruited and therefore they decided to stop the study.⁷

DR. KERN: And, so, the presentation of the PROTECT II trial, was it presented as a positive study or a negative study.

DR. WAKSMAN: Well, I don’t want to go too much into that. There was a lot of data that was presented in the ACC meeting; again, overall the study did not meet the endpoint. So the bottom line, you can call it the neutral study, which is a nice way to say it. But then there were all kinds of analysis that were done. For example, if you extract arthrectomy patients, there were more done in the Impella versus the balloon pump, and there were more rotoblaters used in the Impella versus the balloon pump. The groups were very unmatched; they were not matched groups.

Then if you go and do all those analyses, you may find some areas that you can tease a P value, but I don’t think that this has any scientific value, and people should be very careful. We’re not playing now with numbers or with statistics, this is about patient care. You’re doing a study — the study, I think, has some flaws in the design to begin with — and we actually pointed that out when we were asked to participate in the study. But if the study did not meet the endpoint, then I think all those subanalyses, subgroups, you extract from here, you add to there, and you get a P value, that means nothing. So we have to be careful when we interpret this, other than as a neutral study that you basically cannot adopt any of the … it did not meet the hypothesis, that’s the bottom line.

DR. KERN: So maybe you can tell us, then, what’s our current role for these two support devices in your practice in interventional cardiology?

DR. WAKSMAN: I think that, in the past we used to have more support with assist devices or supportive hemodynamic devices. Angioplasty became simpler. The stents are more deliverable, it’s very quick, we don’t have to go with 10 minutes’ balloon inflation to support the vessel. So I think the number of patients that actually need it has been dropped. The other thing is, we had pretty good experience with balloon pump. As long as we place it ahead of time. So, what we published in another paper: If you do it intentionally, if you suspect you have a patient with high risk, and you put a balloon pump, you’re going to go very well with the balloon pump, and it will work for you.

Therefore, we feel that while the Impella has maybe as good results as the balloon pump, when you compare and contrast the ease of use, the cost associated with it, there is no justification to switch strategy from the intraortic balloon pump to Impella, as long as you don’t have a study that supports superior results with Impella. That study has not been shown, I suspect there will never be another study like that. There is no labeling from the FDA, the devices are approved based on 510(k).

So the bottom line is that we, as a strategy, are using the balloon pump for high-risk PCI if we feel there is a need for support.

DR. KERN: I know you do use Impella on occasion. Where do you find that of most use?

DR. WAKSMAN: I think patients with cardiogenic shock, the use maybe, again, has to be proven clinically, but we feel, for some of the patients with cardiogenic shock, the balloon pump is not sufficient for them. We actually, in this meeting, we presented an interesting abstract, actually yesterday, that actually compared the balloon pump, the Impella, the Tandem Heart, the ECMO device and the mini-LVAD. These are small groups of patients, the groups are not matched. But it turns out that neither the balloon pump or the Impella are doing a lot of differences in terms of the patient with cardiogenic shock. The big difference is — including the Tandem Heart — the big difference is when you use ECMO or mini-LVAD. So you have to be very aggressive with those patients to see a big difference. But if you asked our practice right now, we use the Impella primarily for those patients with cardiogenic shock, and we try to do it earlier rather than later, because later down the game, it’s sometimes too late no matter what you use.

DR. KERN: Well, those are great insights for us on this. And I think the PROTECT II trial was of interest and I think you’ve really addressed the issues that readers are going to have to face when they look at this data. So I want to say thank you and best of luck.