A Rapid-Fire Review of Four Big Trials From ESC 2014

; E. Magnus Ohman, MD


September 12, 2014

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SIGNIFY: Ivabradine Implications for EMA

Robert A. Harrington, MD: Hi. I'm Bob Harrington from Stanford University, and I'm here at the European Society of Cardiology (ESC) meetings with my friend and colleague Magnus Ohman from Duke University. Magnus, thanks for joining.

E. Magnus Ohman, MD: It's great to be here.

Dr Harrington: We've been here in Barcelona for a couple of days now, and certainly there has been no shortage of interesting information, has there?

Dr Ohman: No. This has been a great meeting. A lot of different areas had important trials.

Dr Harrington: Yeah, it really is an interesting meeting for that. We are going to talk about at least three trials right now sort of in rapid fire, one in heart failure, one in stable coronary disease, and maybe another one in heart failure. If we have time, we might even venture into yours and my field, which is interventional cardiology.

Dr Ohman: Right. Maybe we can start off with the stable coronary disease trial, which really is interesting to me -- the SIGNIFY trial.[1] This is a drug, ivabradine, that we don't have in the United States that is approved for the treatment of heart failure and chronic angina outside of the United States. Essentially it was a very large trial that randomly assigned patients with stable coronary disease without heart failure. Overall, the trial was neutral, but the paradoxical thing was that in a large subgroup of 12,000 patients with angina, they actually found that there was a significant increased risk for death and myocardial infarction.

Dr Harrington: Associated with the therapy.

Dr Ohman: Yes. And obviously a therapy that is already being used means that there are implications for physicians in Europe who have the drug, and how they're going to handle this is quite interesting. It is interesting because heart failure was not tested here.

Dr Harrington: Right.

Dr Ohman: That is another area that obviously is important. But I thought that trial was very informative and controversial.

Dr Harrington: Very controversial, and an interesting trial or an interesting drug in that it acts by slowing down the heart rate, at least in part we think, but different from a beta blocker. It's not a beta blocker.

Dr Ohman: Right, right. It basically slows the heart rate through the sinoatrial (SA) node, through a channel in the SA node -- it is very specific for that. What was interesting in the study was that there was a high rate of atrial fibrillation in the group who got the drug that slows the SA node.

Which may be surprising. Then what do we do now? The drug is not available in the United States. The US Food and Drug Administration is going to have some things to think about. Obviously the European Medicines Agency has announced here that they are investigating how this should be brought forward.

Dr Harrington: It's always a challenge when a drug is on the market somewhere in the world for some indication; and then in a related area but maybe not the specific area for which it's being used, the drug either doesn't work or in this case might even be associated with worse outcomes. This would be one case where I would say there is more to come.

Dr Ohman: Yes, absolutely.


Dr Harrington: Let's stick in the realm of coronary disease and talk about SOLID-TIMI 52.[2] This was the TIMI trial looking at the novel anti-inflammatory inhibitor of Lp-PLA2. I was involved with the STABILITY trial,[3] the earlier trial with darapladib that missed on its primary endpoint but had some interesting secondary findings, suggesting that while there's not a major benefit of the drug, perhaps there was some signal. We all were awaiting SOLID. Absolutely nothing. No benefit of the therapy over placebo was seen, and participants had a lot of distressing side effects, including gastrointestinal side effects.

Dr Ohman: This was disappointing because both trials were neutral essentially, targeting one specific aspect of the inflammatory process. I hope people don't walk away saying that inflammation in coronary disease is dead.

Dr Harrington: Yes, I hope people don't say that. You've said it nicely; it's one specific marker that this drug attacks. We knew from the earlier studies that maybe there's some reduction in the necrotic core of plaque,[4] but we didn't know much more than that, did we?

Dr Ohman: No. Obviously there will be a lot more to come out of this; there are trials going on with methotrexate that could be important. This is an emerging field. Stay tuned. There's going to be more in this sphere. Maybe we'll talk a little bit about this. All of the drugs are nonspecific. They block many pathways. Think of aspirin and heparin potentially, statins, but now we have this specific drug, and it failed. That doesn't mean that the whole area is out.

Dr Harrington: Certainly from the STABILITY steering committee perspective, there was great disappointment that the therapy didn't seem to add value. Again, we saw some intriguing signals in some subgroups, but there is all the usual treachery associated with looking at secondary analyses. We were waiting anxiously to see the SOLID results. I'm glad you put the caveat around it. This does not mean that we shouldn't be interested in anti-inflammatory agents that might modify plaque.

Dr Ohman: Right.

Dr Harrington: You and I have spent so much time on antithrombotic therapy. In many ways, antithrombotic therapy is either leveling out in terms of any additional benefit or at most maybe providing some incremental benefit beyond what we've already added over the years. But we do need some new approaches, don't we?

Dr Ohman: I think the next phase of this -- and we have, to some extent, started this phase -- is whether we should replace our existing armamentarium; heparin with bivalirudin, for example. Should we replace aspirin with something else? The inflammatory process plays into that. Aspirin has an anti-inflammatory component to it. The question is: Is this the right way? As we move forward essentially blocking one pathway, is that enough? Time will tell.

Dr Harrington: Yeah, time will tell us. I mean, it has been interesting over the years, hasn't it? As you've indicated, there are a number of drugs that act through multiple pathways, or at least through pathways that we don't necessarily all understand, and the statins may be an example of that. These drugs that have these broad effects, nonspecific effects -- as you've mentioned, aspirin, heparin, warfarin -- they work pretty well.


Dr Ohman: Yeah. So, on that theme, we have heart failure trials here, some very important ones.

Dr Harrington: Yeah. Let's talk first about the one replacing a standard medication.

Dr Ohman: Yes.

Dr Harrington: Who would have thought that angiotensin-converting enzyme (ACE) inhibitors could ever go by the wayside? They have been a cornerstone for a decade.

Dr Ohman: Yes. The PARADIGM-HF trial[5] had a highly, highly significant reduction in the primary endpoint, a 20% relative risk reduction in favor of this compound that blocks several pathways. Here we have something that can benefit our patients with heart failure. This was in patients with severe heart failure, New York Heart Association class II all the way down to class IV heart failure. I thought that was fascinating.

Dr Harrington: Yeah. It's really that spectrum of moderate to severe heart failure for which ACE inhibitors, as I've said, have been cornerstone therapy. Now we have this new agent that combines effects on the angiotensin receptor pathway, but along with some increase in natriuretic peptides, which lead to a vasodilatory state, going up against really one of the granddaddies of them all, enalapril.

Dr Ohman: Right, the first ACE inhibitor.

Dr Harrington: You have the therapy that we've used for decades that has been well studied, well characterized, a big trial. When a number of months ago the trial was halted prematurely for benefit, we were all anxiously awaiting these results. It was not disappointing, was it?

Dr Ohman: No. The results are absolutely conclusive. We're always cautioning people if a trial is stopped early because they tend to overestimate the effect. But the effect size here was so dramatic on top of standard therapy. It's not like it was vs placebo -- a lot of patients had beta blocker. They were all very well treated.

Dr Harrington: It was a very well treated patient population. The investigators did a very nice job. I think rightly, you brought up that caution that when you do stop a trial early, the concern is that you're sort of at an extreme point, and that's why it was stopped. As we all know, these estimates bob around a bit during the course of accruing more data. But as you said, the effect here was so extreme. Milton Packer took great delight in counting out the zeroes in the P value yesterday, didn't he?

Dr Ohman: Yes.

Dr Harrington: You and I have worked in trials for a long time. You don't present many trials that look that good.

Dr Ohman: No. It's like an order of magnitude difference.

Dr Harrington: Yes. Certainly in ischemic heart disease, if you get two zeroes in your P value, you're pretty excited. This one I think had six or seven. It was a very highly significant result and a significant result on the most important endpoint of all, which is mortality.

Dr Ohman: Yeah, that one's big.

Dr Harrington: Fewer people dying. That was pretty extraordinary. Magnus, we've been talking about really large clinical outcomes studies.

Dr Ohman: Yes.


Dr Harrington: One of the trials that you and I were chatting about offline before we started was a really intriguing study of less than 100 patients called NECTAR-HF.[6]

Dr Ohman: This is in the field of vagal nerve stimulation. It's interesting to me because a long time ago Karl Swedberg and others started using beta blockers for heart failure, and everybody said this is crazy, but of course it turned out to be the cornerstone of what we do. Of course, there is the yang of that, which is the vagal nerve. There are some really interesting basic physiology studies that have been done for a long time by no less than Peter Sleight, who was so famous for all of his heart attack work.

Dr Harrington: Oh, I didn't know that Peter had been in this field.

Dr Ohman: Yes, and Peter Schwartz from Italy.

Dr Harrington: Okay.

Dr Ohman: For maybe 20 years, they've been saying that the vagus nerve is really important in heart failure. A couple of trials were presented here. The first trial was actually looking at whether you should stimulate the right or the left side. Of note, the right side has more effect on heart rate. The left vagus side nerve stimulation has more effect on the left ventricle (LV) or myocardium, basically suggesting that that side is more important for LV dysfunction.

The NECTAR trial, which was the trial of about 100 patients, a small number of patients, looked at LV function. It was the first blinded trial looking at LV function with echo. It showed no significant difference.

Dr Harrington: This is with an implant stimulatory device.

Dr Ohman: Exactly, placed here.

Dr Harrington: And they did a sham procedure.

Dr Ohman: Yes, a sham procedure in a blinded trial, which is a very elegant design. It showed no effect on LV function.

Dr Harrington: That was the primary endpoint.

Dr Ohman: That was the primary endpoint. But here's the nugget. There was significantly better quality of life. We haven't seen this before. You will recall CRT or cardiac resynchronization therapy. Same initial process. There is a large outcomes trial that is being conducted right now that is looking at this. I think this is a very interesting field. The neurologic part of the whole regulation of the heart is something we put on the back burner since we got the beta blocker. It's now emerging forward.

Dr Harrington: I think it is Dr. Braunwald who tells this story of the stimulation of the vagus in the setting of treating angina, correct? He recounts a story of a patient having ST elevation and treating him with the stimulation and really making some important observations, years ago when he was at the National Institutes of Health.

Dr Ohman: Right. Physiology 101 may be coming back again. It's too early to say, but I was fascinated by this whole concept.

Dr Harrington: It's also a good example of some of the challenges with the intermediate outcomes. In this particular case, I think they were looking at systolic volumes as a marker of LV function. While that didn't change, patients did feel better. So, how to reconcile those two or whether we even need to reconcile them I think will require more investigation. Well, Magnus, as always, it's fun to talk with you. There's a lot more interesting stuff to go over the next few days here in Barcelona at the ESC. Thanks for joining me here today.

Dr Ohman: That's great, Bob. Thank you.


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