The Cardiology Show From ESC 2015 with Dr Valentin Fuster

Moderator: Valentin Fuster, MD, PhD; Panelists: Carina Blomström-Lundqvist, MD, PhD; M John Chapman, PhD, DSc; John GF Cleland, MD; Michael J Mack, MD; Roxana Mehran, MD

Disclosures

September 02, 2015

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Editor's Note: From the European Society of Cardiology Congress in London, England, Dr Fuster and panel discuss a leadless pacemaker, cyclosporine and reperfusion injury, resistant hypertension treatment pathways, high-sensitivity troponin for early MI diagnosis, and yet more data on antiplatelet and antithrombin strategies in patients undergoing PCI.

Introductions

Valentin Fuster, MD, PhD: I am Valentin Fuster from New York and we are in London. What a beautiful city, and how much it has changed over the past few years. Let's get to business.

We are here in the meeting of the European Society of Cardiology, where thousands of papers were presented. There were 27 hot-line trials, and we are going to touch on some of them. But before we do this, let me introduce the professors. On my right, Prof John Cleland, professor of cardiology, Imperial College in London in Royal Brompton in London. Then my friend and colleague Prof Roxana Mehran, professor of medicine and head of research intervention at the Mount Sinai Medical Center in New York. Prof Michael Mack, chair of cardiovascular service line at the Baylor Scott and White Health in Plano, Texas. Prof John Chapman, research professor, University of Pierre and Marie Curie in Paris, and certainly an expert, director emeritus interim in dyslipidemia and metabolism in Paris. And here on my immediate left is Prof Carina Blomstrom-Lundqvist from Uppsala University in Sweden.

Great people. Each of has their view. Let's see how we interact. We are going to move from the electrical field into hypertension and then into coronary disease, diagnostics, antithrombin therapies, and I don't know if we will have time to make a few comments about some of the trials that we won't be discussing in detail.

LEADLESS II Safety and Efficacy of a Leadless Pacemaker

Dr Fuster: Let's begin with the first study that I would like to present. The so-called percutaneous implantation of an entirely intracardiac leadless pacemaker. This was presented by our colleague Dr Vivek Reddy from the Mount Sinai Medical Center in New York representing the LEADLESS II study investigators.

When I was a medical student they were just starting to talk about transvenous pacemakers. Now in 2015, the pacemakers have gotten smaller and smaller, but still you have two problems: a subcutaneous pocket and a lead going to the heart. The lead to the heart can fracture, get infected, become dysfunctional. You can have similar problems with the pocket: hematoma, infection, nonfunctioning. The solution? A tiny device that you can insert through the femoral vein, no surgery, no pockets. This is what we are talking about.

This device was first looked at in a feasibility trial that was published in 2014.[1] I believe there were 30 or 40 cases, in which this little device implanted in the right ventricle did well. The study that we are discussing today is the LEADLESS II study.[2,3] It's a nonrandomized observational study of the first 300 patients with 6 months of follow-up. Now the primary efficacy end point was an acceptable pacing threshold and also an acceptable sensing amplitude. I'm not going to give you numbers because I'm not an electrophysiologist. But you know what I'm talking about.

The primary safety end point was freedom from device-related serious adverse events through 6 months. In the intention-to-treat analysis, the primary efficacy end point was met in a primary cohort of 300 patients (there were just over 500 patients followed for a shorter period of time, but let's concentrate on the 300 patients that reached 6 months) In 90%, the pacemaker was working very well in terms of thresholds and so forth. And for the safety end point, 93% did well. Close to 7% had complications, including dislodgement with percutaneous retrieval in 1.7% with no emboli to the head. This is something we should talk about for a moment. Cardiac perforation occurred in 1.3%, and then there were other minor problems.

Now the interesting aspect is the conclusion that when you compare it with the old transvenous pacemakers, which we are told have a complication rate of one in 10 patients, this leadless pacemaker has a complications rate of one out of 15 patients. To summarize, the leadless pacemaker met the specified pacing and sensing requirements in the large majority of patients, and the device-related serious adverse events were a little bit lower than what we have faced with the transvenous pacemakers.

Carina, you are an EP, are you excited?

Carina Blomstrom-Lundqvist, MD, PhD: This is an exciting development, given the difficulties we face with the transvenous leads. As you pointed out, we see quite a few infections and we have problems extracting the leads, especially the CRT leads. I don't think we have the same problems with the single-chamber–device leads because it's a simpler device. I can foresee this device developing so that we can put the chamber device also on the atrial level and perhaps also use it to complement a subcutaneous ICD.

Dr Fuster: Prof Mack, what do you think?

Michael J Mack, MD: I also think it's a big deal. It is a first-in-class device and as such there are some concerns. Cardiac perforation should be a never event, and it happened in about 1.5% of patients. Dislodgement is a concern. I think two of the dislodged devices went to the femoral vein and one to the pulmonary artery. So that's a concern. But for a first-in-class device it's very promising. It's also a single-chamber device. It's incapable of remote monitoring. All of that will come later. There are other devices coming in the field with different methods of fixation. For a first-time-out, first-in-class device it's very exciting.

Dr Fuster: Roxana, you're an interventionalist. What do you think about this little thing in the right ventricle?

Roxana Mehran, MD: Obviously, you worry about long-term events. We only have 6 months of data. It is absolutely exciting that we have demonstrated feasibility with some efficacy and safety data, but it's only 6 months. The long term is something that we need to better understand. What happens when the battery life is out? How do you deal with that? And all of the important issues regarding pacemakers in general. But I'm very hopeful.

Dr Fuster: John, it's not your business, though. You're in cardiac failure putting synchronous pacemakers all over the place. What do you think?

Dr Cleland: I think this is the right direction. As Dr Mack has said, a good first attempt. It being a single right ventricular pacing device limits it somewhat to perhaps people with atrial fibrillation and very slow heart rates. You could see this as being perhaps the optimal device depending on the long-term safety follow-up.

The real excitement will be with the next generation—a standard right-sided pacing system combined with a left ventricular leadless device. Clearly we're going to have to make sure that it doesn't embolize (it might embolize to somewhere more risky), but there is a lot of animal evidence to suggest that left ventricular endocardial pacing is superior to epicardial pacing. For cardiac resynchronization with a leadless device in the left ventricle that talks to a fairly standard system on the right side will be the next generation. Whether we'll get a smart-enough device that is safe to fix to the atrium and both ventricles may be a bit further down the track.

Dr Fuster: Carina, how does this work? If I want to run a mile and my heart rate goes up, and I need the pacemaker, and I am told that temperature plays a role. What if I have a high temperature?

Dr Blomstrom-Lundqvist: I don't think this pacemaker is that advanced to have a rate-response function corresponding to a dual pacemaker. Is that what you're referring to?

Dr Fuster: Yes.

Dr Blomstrom-Lundqvist: That's the difference with this vs a standard pacemaker. You would give this type of pacemaker to patients with a slow atrial fibrillation, but not to a patient with an AV block because you would have dyssynchronies. That's a problem still. We'll need a corresponding atrial chamber device to go with it.

Dr Cleland: The risk of perforation with an atrial device must be higher.

Dr Blomstrom-Lundqvist: Absolutely, with this very large size, but in 5 or 10 years maybe it could be possible. A more near-term development is to combine a subcutaneous ICD without any transvenous leads with this pacing capability, provided it can give antitachycardia pacing. Then you would have a totally leadless ICD system. I think that would be perfect for the primary prevention of sudden cardiac death.

Dr Fuster: So how many of the pacemakers that we implant today that the patient would be suitable for these types of pacemakers with AV block? Is it about 15% to 20%?

Dr Blomstrom-Lundqvist: Approximately. It's not the high volume because it's a single lead in the ventricle.

Dr Mack: But we're describing all the desirables, the wanna haves. I don't think we can forget that there is a clinical unmet need right now that this fulfills. That's patients who don't have vascular access, all the patients who are undergoing lead extractions either because there's no way to get another lead in or because they're infected, etcetera. It does fulfill an immediate need also while the next iterations come along.

Dr Fuster: John? What do you think?

M John Chapman, PhD, DSc: Well the immediate question in my mind is will technology enable nonleadable recharging of the battery because it would seem to me a critical question. How would we recharge the system?

Dr Mack: We've been trying to address that for years with mechanical circulatory assistance and trying to figure out transcutaneous energy transmission. It's finally getting there, but that's been 20 years trying to figure out how to transmit energy without generating heat across the skin.

Dr Cleland: But that was for subcutaneous devices, and this is intracardiac, so that's going to be a bigger ask. But we have lots of energy sources. MRI is a pretty good energy source. You can generate heat with MRI. You can generate heat with focused ultrasound, and of course the body itself uses a huge amount of energy, which it just radiates as heat. If somebody can come along and do something environmentally smart, to use all of that wasted heat.

Dr Fuster: We can summarize by saying this is a great advance, perhaps the question is to be cautious. As Roxana mentioned, this is a very short follow-up on a device that is just sitting freely in the ventricle. It's not like a valve that is implanted with sutures and so forth. Hopefully it will not be a problem, but the issue of dislodgement is a bit of a question.

PATHWAY 2: Algorithm-Based Hypertension Therapy

Dr Fuster: We are going to talk about hypertension now, and the PATHWAY study[4] an optimal treatment of drug-resistant hypertension. And this was presented by Dr Bryan Williams from London and was sponsored by the British Heart Foundation. This is a great study.

First, let's talk about resistant hypertension. We have been talking about it for a while in relation to the sympathectomy approach and the failures of renal denervation. About 10% of people with hypertension have resistant hypertension, defined as high blood pressure despite three drugs, the so-called ACD: the ACE inhibitors, calcium blockers, and I don't know if the D is for diuretic or Dyazide, I guess it's for diuretic. Spironolactone was seen as feasible in this setting. It's a drug that we give to spare potassium, and I never thought of it as a drug that could drop blood pressure significantly.

This was a very elegant study the way it was designed. There were 335 patients with resistant hypertension who received the different medications sequentially. Then the investigators looked at how the patients did over a cycle of 12 weeks, in terms of blood pressure, an average of week number 6 and week number 12. They used spironolactone 25 mg to 50 mg, which was the key drug. Then they use the beta-blocker bisoprolol 5 mg to 10 mg, the alpha-blocker doxazosin 4 mg to 8 mg, and then a placebo, and it was done in rotation. It was very clever in terms of the end point. The end point was systolic blood pressure (SBP), and they looked at the difference between the systolic blood pressure in the spironolactone group and that in the placebo group.

If that difference was significant, then they looked at the blood pressure between the spironolactone and the average of the other two drugs together. And then it was compared individually against bisoprolol and doxazosin. The findings were very significant in favor of spironolactone vs the placebo. In fact, the systolic blood pressure dropped by 8.7 mm Hg. For spironolactone vs the combination or the average of bisoprolol and doxazosin, the difference was 4 mm Hg, and it was about the same compared individually with bisoprolol and doxazosin.

This is great in terms of resistant hypertension, but I have a question, when you look at an 8-mm-Hg drop in SBP, is that enough?

Dr Chapman: Well, this is actually a provocative question, Valentin, in the sense that my own question is, I'm sorry I missed the presentation today by Bryan, but is this peripheral or is this central systolic?

Dr Fuster: Peripheral.

Dr Chapman: It's a relatively small change in the context of the typical level of systolic that one would see in an individual with essential hypertension. What was the mean systolic at baseline in this study?

Dr Fuster: It was about 150 mm Hg to 160 mm Hg [Editor's note: Mean home SBP was 148 mm Hg and mean clinic SBP was 157 mm Hg]. What do you achieve in terms of impact? This is really my question.

Dr Cleland: One mistake we often make in our trials is that we look at the average effect, but of course only one person has the average effect and half of them have less than the average effect and half of them have more. Probably for some patients this was the solution for their resistant hypertension. For other people it may be that they didn't take it—one of the big reasons for resistant hypertension is the patients not actually taking their medication.

Dr Fuster: I want to make a comment about the paper because they say only 15 of these patients would be eligible for renal denervation, and this bothers me because obviously what we are discussing is the impact. I'm not entirely sure only 15 of these patients would be considered candidates for denervation.

Dr Cleland: There aren't any patients indicated for renal denervation with the present efforts.

Dr Fuster: I'm speaking about originally [before SYMPLICITY HTN-3]. This is why what I'm saying is a great study, and I think the results are quite interesting, but what is going to be the impact?

Dr Cleland: I'm a strong advocate of aldosterone antagonists. Obviously, I'm mainly interested in heart failure and we've shown that these are disease-modifying drugs in the heart-failure setting. I've long used spironolactone for hypertension. I don't think that we use it often enough. I think that it would be great to have a major outcomes study of aldosterone antagonists in hypertension to finally prove that it should be up there with the other first-line antihypertensive agents. Although maybe hydrochlorothiazide and amiloride would be just as good in this population as spironolactone.

Dr Fuster: Roxana?

Dr Mehran: There are a lot of issues with this study. I know that everyone loves it and it's nice because you go back to the future with an old drug that works very well. We know it works great.

Dr Fuster: And it's cheap.

Dr Mehran: It's cheap. It works great in heart failure, moves fluid like there's no tomorrow, potassium sparing, all those good things. But let's take a look at the study. They looked for resistant hypertension, and from what I remember it was about 475 patients [436 patients were screened] and at the end they only had 335 evaluable patients, and it was not a randomization. The patients were their own controls going through this cycle of different treatments.

Dr Fuster: Yes.

Dr Mehran: The degree of reduction in blood pressure was at best modest, to me. It may make us feel good, but the sham control of the renal-denervation studies had an 11-mm-Hg reduction in blood pressure over a 6-month period. In my mind we shouldn't get too excited and think we can just give [spironolactone] to patients and they're going to be okay. I'm a little more reserved.

Dr Cleland: We have active controls as well in this study. I've long thought that doxazosin is not a very good drug for hypertension, and this study sort of reinforced that.

Dr Fuster: Carina, how do you react to this discussion?

Dr Blomstrom-Lundqvist: It seems like a very modest blood-pressure reduction. That's my first impression.

Dr Mack: Do you want to ask a surgeon about hypertension? Like you, I have always thought of spironolactone for potassium sparing, and the fact that it did show some benefit in drug-resistant hypertension, albeit modest, is very much a positive. I think we should think of it more in the treatment of hypertension than we have previously, it's another building block in the armamentarium. It's well-known and it's inexpensive, which is even better.

PATHWAY 3: Single vs Combination Diuretics in Essential Hypertension

Dr Fuster: Well, actually your question brings me to the next paper that we will discuss very briefly, which is also about a potassium-sparing drug, amiloride. It's from the same group and is called PATHWAY3.[5] When you use blood-pressure medications (thiazides and the like) you may drop the potassium level, and you may cause prediabetes or increasing blood sugar. And the question is, could a drug that is potassium-sparing counteract this?

They designed a study using the following regimens. These were 440 patients with uncontrolled hypertension. The SBP was higher than 140 mm Hg and they also had at least one component of the metabolic syndrome. The patients were randomized to amiloride 10 to 20 mg, the combination of this drug with hydrochlorothiazide, or hydrochlorothiazide alone. When the two drugs were given together they dropped the dose in half.

They looked at the 2-hour oral glucose-tolerance test at 12 and 24 weeks and blood-pressure response. What they found is that the combination is better in terms of blood-pressure control even when the dose is lower of each of the drugs. At the same time, the potassium is stabilized and the blood sugar doesn't increase. Basically, the message is that using a potassium-sparing drug together with a thiazide is doing some good. What do you think about this one?

Dr Cleland: It's interesting that with the DASH diet we try to increase potassium as part of the antihypertensive control and now we're talking about retaining the potassium you have. One of the potential benefits of these treatments is potassium retention. We should be concerned with some of the drugs coming out to control hyperkalemia that we don't overcook it because actually a potassium of 4.5 mEq/L in your serum is just about where you want to be.

I think the advantage of amiloride compared with spironolactone is that dangerous hyperkalemia is less common, and the reason for that is because your aldosterone can still work and help you get rid of the potassium. If you give an aldosterone blocker you've blocked your escape mechanism. If you give amiloride you haven't. It might end up being safer or it might end up being just as good.

Dr Fuster: Carina, will you go home thinking more about potassium-sparing drugs?

Dr Blomstrom-Lundqvist: I think so. What struck me is that maybe they will have an effect on atrial fibrillation. Hypertension is a risk factor for atrial fibrillation, and we have patients, especially females with hypertension who are put on antiarrhythmic drugs, [Editor's note: Speaker means to say antihypertensive drugs] and they get very low potassium levels. It's not good. It may be proarrhythmic. So from that perspective it may have positive effects.

Dr Fuster: You found a different way to look at it. John? Any comments?

Dr Chapman: Well as soon as you mentioned metabolic syndrome, Valentin, I immediately think about the interaction between dyslipidemia and hypertension, because we know of course there's nothing better than high systolic BP to drive atherogenic lipoproteins into preferential sites of plaque formation. So was there a background lipid-lowering treatment here?

Dr Fuster: Yes.

Dr Mack: One of the things to take away from these trials that either show no benefit or only a modest benefit is that you really have to get to precision medicine and look at responders vs nonresponders and identify those groups. The way I've always thought of it, be it hypertension or heart failure or mitral regurgitation, is if you took a whole group of patients with anemia and just treated them with vitamin B12, and you say well the whole population didn't benefit or there was only a moderate benefit, but you didn't identify that group with pernicious anemia, then you would have missed the benefit of that treatment. I think that's the way we have to think of these trials and not make blanket statements but try to dissect out who are the potential responders of treatment.

Dr Fuster: I'm impressed that we have a surgeon talking about precision medicine.

Dr Mack: Hopefully we're precise.

Dr Cleland: You make an important point with this idea about responders. That is a very important concept, but it has to be in the context of a clinical trial because differentiating the natural history of the disease from the impact of the intervention is almost impossible in observational studies.

Dr Fuster: We've had two interesting papers so far, or three. One on the diuretics and the other one on the electrical new pacemaker.

PLATFORM: FFRCT-Guided Diagnostic Strategy vs Usual Care

Dr Fuster:Now let's move into the coronary arteries. There's a lot to be gained with CT angiography. And one of the issues is whether measuring [fractional flow reserve] FFR with CT may be a first step in coronary angiography.

This study is called PLATFORM, [6,7] a prospective longitudinal trial of FFRCT outcome and resource impacts, and it was presented by Pamela Douglas. The trial has a complex design, but it basically tests whether measuring fractional flow reserve with CT can allow you to make decisions without doing an invasive coronary arteriogram.

There were 11 institutions with almost 600 patients with recent onset of chest pain. So these patients were ready for an invasive coronary arteriogram. They divided the patients in two groups. One group got usual care by the physician, and the other group underwent CT and they did FFR with the CT. Ahead of time they decided whether the patient would need a coronary angiogram regardless of which group they ended up in.

At the end, the use of the CT/FFR in patients with planned invasive catheterization was associated with a reduction in the rate of finding no obstructive coronary artery disease from 73% to 12%. In other words, the FFRCT resulted in the cancellation or the possible cancellation of 61% of the invasive coronary angiograms.

This is quite interesting, because they looked at function and anatomy in one tool in patients who were scheduled for an invasive angiogram. If you do CT, many of these patients don't have coronary artery disease. Michael, how do you view this?

Dr Mack: I have always loved the concept of combining noninvasive angiography with functional analysis using FFR. It was always going to be the gold standard. If I'm disappointed, it's in how long it has taken to prove the concept and to prove the efficacy. This is another step in terms of getting there, but I wish we were there already. We will eliminate the need for a lot of diagnostic catheterizations going forward.

Dr Fuster: Roxana, what do you think about the FFR? How reliable is it with this technology?

Dr Mehran: First, I want to congratulate Pam Douglas. This is a huge study, a great step forward. But the study has a lot of issues in its design. This is not a randomized study. It's really a descriptive study. We want to avoid angiograms in patients who do not need them—ie, those who have nonobstructive disease. And I think this is a tremendous step forward.

Am I feeling really confident that the CT/FFR is actually going to do this prospectively? First of all, they didn't validate this with a true FFR in the cath lab, which is an invasive measure using a wire down the arteries in moderately obstructed vessels to see if there's a physiological need for intervention. That wasn't done.

Dr Fuster: It was a randomized study of usual therapy vs CT.

Dr Mehran: Actually, it was an intention for an angiography vs patients who were going to have noninvasive testing vs those who were going directly to the cath lab. And in the patients who were going directly to the lab doing a CT/FFR actually reduced those with nonobstructive disease at cath to 16% vs 72%. So it's amazing. It's great. But I think we really are just one step forward. We're not 100% there. I think we've got do the right study in larger cohorts of patients, because if you look at the [patient flow] buckets you have fewer than 100 patients in some of those buckets, which is not enough for a full validation.

Dr Fuster: Carina?

Dr Blomstrom-Lundqvist: What was the radiation dose vs usual care?

Dr Fuster: It was the same, actually. That's an important point. Any comments, John?

Dr Chapman: Yes, we're really in the ballpark of obstructive disease that's reflected of course in the FFR. My concern is positive vs negative remodeling for plaque, because we're always missing the positive remodelers who may have some degree of vulnerable plaque, diffuse plaque. We are still in need of a more reliable imaging technology, which hopefully would be noninvasive to identify those individuals. As we've seen in this meeting, we're moving forward now with some highly efficacious new agents to lower LDL cholesterol, which has recently become causal in the atherosclerotic pathway. So that would be my comment, Valentin.

Dr Mehran: Dr Fuster, can I just make one last point? I think this is hugely important regarding appropriate-use criteria, which is huge for US physicians. It is important to note that interventional cardiologists would be thrilled to have the right patient come to them at the right time for the right procedure. A lot of hype surrounding this study has been that you're going to get fewer coronary angiograms and fewer surgeries and PCIs. But this is not what this is meant to do.

Dr Fuster: I agree.

Dr Mehran: A really important message for everyone who is listening is that this is about finding the right patient. We're put in the corner when a lot of the patients come for a cath and we see normal coronaries.

Dr Fuster: Final comment, John?

Dr Cleland: Do you need to go to FFR, or what were the calcium scores in these patients? Could you actually do sequential imaging so you start with something very simple and quick like looking at the calcium scores? If you've got a calcium score of 0, is it actually worthwhile doing anymore?

Dr Fuster: Except these were patients with onset of chest pain, this is not the population that is stable and comes to see you and you do a calcium score.

Dr Cleland: I know there is soft plaque, and I know theoretically you've got the possibility of plaque without calcium, but I would have liked to have seen simpler procedures, and there's actually quite a few other technologies, including some biomarkers out there that might tell you about plaque burden. And it may well be that those simpler measures tell you that it's not worthwhile doing an FFR in this patient because your likelihood of seeing anything is so low.

Dr Fuster: It's a good point. Simplicity should be our goal in everything. When you have a patient with chest pain you have to be very simple. And I don't think you can go around doing lots of tests. The technology we are talking about is quite interesting. because it's simple and it's telling you the basic things that you need to know. However, when you get into the chronic patient, maybe we'll have something even simpler such as calcium score and so forth, but this is a patient that comes with problems and you have to get the answer quickly.

CIRCUS: Cyclosporine in STEMI patients

Dr Fuster: Now we are going to discuss a study that is interesting because it was a negative result, which was surprising. This is the role of cyclosporine before PCI in patients with acute myocardial infarction. It was presented by Dr Ovize[8,9] from Lyon, and it's an international study on nearly 1000 patients, mostly from France; Belgium and Sweden were also involved.

I know a little bit about this because of work done by many people, including our laboratory, showing that at the end of an acute event about half of the size of the infarct is related to the occlusion, but the other half is related to the reperfusion injury. There's a change in thinking. Can you do something with a reperfusion injury? And there's some experimental data suggesting that this drug, cyclosporine, inhibits cyclophilin D, a major component of the mitochondrial permeability transition pore. Could you reduce injury if you block that metabolite?

Well, this has been shown in animals, it was very consistent, but the human studies have not been so consistent. This study is the most definitive one that I know of. There started with 970 patients with an acute anterior ST-elevation myocardial infarction who underwent coronary intervention within 12 hours of symptoms onset. And before the procedure the culprit arteries received an infusion, a bolus injection of cyclosporine or placebo intravenously.

The primary outcome was death from any cause, worsening of heart failure during initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. I didn't understand what that meant at first, and then I read more carefully, and basically it's a left ventricular end diastolic volume that is about 15% more than it should be. This is important, because the number of events were very high and it's because this single end point increased the number of events. The rate of primary outcome was 59% in the cyclosporine group and 58% in the control group.

In conclusion, cyclosporine failed. Is this the wrong drug? There was a very good editorial [by Hausenloy][10], which we will comment in a moment. Roxana, what do you think?

Dr Mehran: Well, first of all it's a huge study on reperfusion injury, and I was very disappointed. I also felt that when you add this end point that hugely drives all of the events, the noise-to-signal ratio could be elevated. But the clinical end points were no different, either, when you looked at each of the components of the composite end point. So I was hugely disappointed. because I think we've got to do something for these patients. At this point, given this size study with a negative result, I think we have to say no to cyclosporine, unless you feel otherwise.

Dr Fuster: No. The opening of the mitochondria is very complex metabolically, and they're just touching one metabolite. I was interested on the editorial comment because Dr Hausenjoy is an expert in the field of reperfusion, and he raises a concern that is very important. We have seen this in many other occasions. The type of cyclosporine that was used was not the same one that worked in previous human studies, the so-called CicloMulsion. And he asks whether the cyclosporine has the activity of the version that was used before. We've seen this before in other circumstances. Mike, you obviously understand ischemia very well. What is your reaction to this?

Dr Mack: Well, I agree with you that reperfusion is as much a part of the injury as vessel occlusion. There is a huge clinical unmet need. I feel like Roxana; a lot of the air has gone out of the balloon. I'm not smart enough to know whether a different version of the drug is going to make a difference. There's speculation in that editorial that a different route, for instance intra-arterial, may make a difference. But with this trial being profoundly negative it's going to be a big hill to climb to look at this further with either other iterations or other delivery routes.

Dr Fuster: Absolutely. John?

Dr Cleland: This issue about the preparation, whether you actually got the cyclosporine to where you wanted it to be, the dose, and the duration of therapy. Should it have been multidose? Should we have dosed for three days? I don't know. It's disappointing. It's a novel concept, a lot of people are interested in perking up our mitochondria. It's a shame we didn't see some sort of signal that we could work on.

Dr Fuster: Carina, what do you think?

Dr Blomstrom-Lundqvist: It's a very difficult question, because I don't know the half-life, the ideal route of administration, should it be venous route, enteric route. Difficult to say.

Dr Fuster: John?

Dr Chapman: What immediately occurs to me is that we could do in vitro experimentation to compare these different forms of cyclosporine and perhaps get some further information.

Dr Fuster: That's a good point to test it, because it worked in most of the animal models.

MATRIX Antithrombin: Bivalirudin ± Infusion vs Heparin in PCI

Dr Fuster: Well, a little disappointment, and now we have a paper that may be disappointing for some and great news for others. Let's move to the MATRIX[11,12] study.

Sitting on the editorial board of [the Journal of the American College of Cardiology] JACC, we get so many papers about the right antithrombotic to give with PCI: bivalirudin, heparin, [GP] IIb/IIIa. After a year, I was wondering why there are so many papers about this. It means we don't have the answer.

Dr Cleland: Or that the difference between them is so small.

Dr Fuster: Roxana, my understanding is that bivalirudin was very big in the States but there was some increased thrombosis. Is that not correct? It is better in terms of bleeding than heparin.

This is a very large study. About 7000 people with acute coronary syndromes (ST-elevation and non-ST elevation), and they randomized these patients to bivalirudin or unfractionated heparin. But since they were concerned about the thrombotic phenomenon with bivalirudin they randomized that particular group to a post-PCI infusion or no infusion. And then they made lots of comparisons.

The primary outcome was major adverse cardiovascular events [MACE] when they compared heparin with bivalirudin in general. And the MACE were a composite of death, myocardial infarction, or stroke. And then they look at net adverse clinical events, which is the same but you add bleeding.

And then they divided the bivalirudin patients into two different groups. The primary outcome was urgent target vessel revascularization and stent thrombosis, etcetera.

So let's go into the results. No difference on anything. Bleeding, net events, adverse events, randomization to bivalirudin infusion dose. So Roxana, what do you make of all this?

Dr Mehran: Having spent the past decade of my life on this topic, Dr Fuster

Dr Fuster: I only spent 1 year.

Dr Mehran: Let me explain what I think. First of all, MATRIX was an incredible study done by Italian investigators who did this on their own to answer a very important question, because previous trials were looking at bivalirudin vs heparin plus a glycoprotein IIb/IIIa inhibitor because everybody was afraid of the periprocedural infarcts, etcetera. And so GP IIb/IIIas were always being used. Now, with the more potent antiplatelets, we realize bleeding is not good and there is more bleeding associated with GP IIb/IIIa and we need to go to something else. Bivalirudin vs heparin plus IIb/IIIa has always shown a major reduction in bleeding complications, as you would expect, because there's no IIb/IIIa involved. Everyone was worried that bivalirudin was going to increase major adverse clinical events in the absence of GP IIb/IIIa. The results of MATRIX are very consistent with everything we had seen before.

The study was a 2x2 factorial design, radial vs femoral. That was one piece of it. Then it was also heparin vs bivalirudin, and in the heparin arm 25% of those patients required a GP IIb/IIIa. At this meeting, they presented the bivalirudin-alone arm with a subrandomization of a continuous infusion vs stopping at the end of the procedure. And we've known that there's more acute stent thrombosis with bivalirudin. This is nothing new. What is totally surprising to me is that the continuous infusion actually had a higher rate of subacute definite stent thrombosis. Not acute but subacute definite stent thrombosis, there were 13 vs three events. I tried to understand this and I actually called the investigators and asked, "Is this a typo? Are we sure this is correct?" It is correct, and they were puzzled by it. But then when I dug deeper into the paper I saw that in the patients who received the continuous infusion 60% of them received a very low dose of 0.25 mg/kg/hour vs the other 39% who received 1.75 mg/kg. The 0.25 mg/kg/hour is a very low dose for an infusion. I am not sure how to interpret this, but previous trials have shown that a continuous infusion [is beneficial].

Dr Fuster: A large number of heparin patients received GP IIb/IIIa, isn't that correct?

Dr Mehran: Yes, 25%. But it is important for everyone to note that bivalirudin was associated with a reduction in mortality in this large MATRIX study. Bivalirudin reduced bleeding, but it increased stent thrombosis, and it was not helped by a prolonged infusion. I think that's the message of this paper. Where we go from here I'm not so sure. I think many might consider the cheap heparin going forward with the more potent agents. But we'll see.

Dr Fuster: So we'll continue to see papers on this subject, unfortunately.

Dr Mehran: Yes, you'll be getting lots of papers. I'll be working on that.

Dr Cleland: So when you said there was a mortality difference? What was the absolute reduction?

Dr Mehran: The absolute reduction was small, about 1%. But it did reach statistical significance with a P value of 0.04, so just borderline. [Editor's Note: All-cause mortality at 30 days was 1.7% for the bivalirudin group vs 2.3% for heparin.]

Dr Cleland: Well, that's not small for an interventional trial.

Dr Mack: I think one of the things you can say about everything we've talked about, as well as some other trials here, like the SERVE-HF trial,[13] is that we've always been criticized in medicine for not reporting negative trials. And we've seen a lot of negative trials at this meeting, which I think are just as valuable in clinical practice as positive trials.

Dr Fuster: I agree completely. In fact, the two trials that we just talked about give us a lot to think about.

OPTIDUAL: 12 vs 48 Months of Clopidogrel after DES

Dr Fuster: We have a few minutes; I would like just to touch on a couple of things and only a touch. And that is the first one is the dual antiplatelet therapy saga. How long?

Dr Cleland: You get even more papers on that actually.

Dr Fuster: After these presentations, I think we are going to receive many more. There are two studies in this meeting about dual antiplatelet therapy. One of them was a meta-analysis[14], which the TIMI group participated in. And it was in patients with acute coronary syndromes. That makes a lot of sense because we are learning that long therapy is perhaps justified in patients who have complex disease following PCI, and certainly acute infarction falls into that category. That meta-analysis had similar conclusions to the DAPT[15] study. The conclusion read: "Compared with aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior myocardial infarction decreases ischemic events, including significant reduction in the individualized end points of cardiovascular death, recurrent MI, and stroke. Dual antiplatelet therapy beyond 1 year increases major bleeding but not fatal bleeding or noncardiovascular death." So it's in favor of longer duration, but these are patients with myocardial infarction.

Then we come to the randomized study from France, Dr Gerard Helft presented the OPTIDUAL[16] randomized trial. Basically, it's not dissimilar to the DAPT study. These were patients after PCI, high risk, moderate risk, low risk, and the results were not different if clopidogrel and aspirin were given beyond 1 year vs aspirin alone. Whether the complexity of the disease makes a difference or not, I'm just presenting the two sets of data from this meeting. Any comments?

Dr Mack: Roxana and I have both served on the update to the DAPT guidelines committee, and I must say over the past 6 months I've learned more about DAPT than I ever wanted to know.

Dr Fuster: Can you summarize what you learned?

Dr Mack: It's a trade-off between thrombosis and bleeding. That's what it basically comes down to.

Dr Fuster: And you have to make the decision.

Dr Mack: Now as editor you are going to begin seeing papers looking at DAPT in [transcatheter aortic-valve replacement] TAVR patients. We're working on a very important trial design now called the CLOE trial of looking at aspirin alone vs dual antiplatelet therapy for transcatheter valves.

Dr Fuster: We talk a lot about hemorrhage recently. Ten years ago, we didn't talk about hemorrhage so much.

Dr Mehran: Bleeding is bad. And many have ignored it, and I think it's time to recognize it. Patients don't want to have bleeding. So it's a good thing that we're talking about it.

Dr Fuster: What is surprising in this study from France is the bleeding didn't increase mortality because in general bleeding is associated with mortality for all of the reasons that we know.

BACC: MI Using a High Sensitivity Troponin I 1-hour algorithm

Dr Fuster: I'd like to comment about this last study on troponin.[17] We know troponin very well. We use it every day. There's an algorithm that actually comes from the ESC guidelines, and I would like to read it.

The guidelines recommend measuring high-sensitivity-assay troponins directly after admission and after 3 hours detecting elevated levels based on the 99th percentile of the specific assay together with an increase or decrease in the troponin level as you go over the 3 hours. This paper shows that 1 hour is enough [with this high-sensitive troponin I test], and we should change the algorithm. The high-sensitive troponin I cutoff of 6 ng/L performed better compared with the 99th percentile, 27 ng/L [for the standard troponin T test]. Basically we are coming up with something important practically. We can use an assay that within an hour you really can triage patients. It's an interesting study. I'd like to see the full paper to really judge it in more detail, but I think it's interesting.

So I would like to—we have 1 minute and I would like to conclude by saying that this was an interesting meeting in terms of the trials. I don't think there was anything that made me 100% excited, but maybe we got 70% excited about the trial on the leadless pacemaker. Dr Cleland was very excited about the potassium-sparing agents. Then we had two negative trials, the cyclosporine trial and MATRIX comparing heparin and bivalirudin. The CT angiography trial was a good step forward, even in terms of economics by avoiding unnecessary angiograms in arteries that are completely normal.

Panelists Top Picks

I just want to finish by asking all of you 15 seconds each, and that is what do you think of everything that we discussed did you feel most excited?

Dr Cleland: Well of the things that we talked about I think the leadless pacemaker has huge potential, particularly to develop CRT and endocardial—

Dr Fuster: Potential for the cardiac-failure experts.

Dr Cleland: Yes. The other thing is preventing heart failure for which, you know, treatment is good, prevention is better.

Dr Fuster: You can only pick one. I think you said the pacemaker.

Dr Cleland: I would go with that as number one.

Dr Fuster: Carina?

Dr Blomstrom-Lundqvist: Well I would say maybe the CT to diagnose ischemic heart disease.

Dr Fuster: Fantastic, an electrophysiologist can do CT.

Dr Blomstrom-Lundqvist: Because in the long run you may develop a small ambulatory device and you could have the general practitioner diagnose the patient even outside the emergency department, allowing an early diagnosis so the patient doesn't have to travel to the hospital.

Dr Fuster: Roxana, it's your turn.

Dr Mehran: The leadless study is very exciting but I think I'm more excited about the opportunity for us to do appropriate caths on patients. They're now coming with angiographic FFR too.

Dr Fuster: Getting into the microvasculature.

Dr Mehran: Exactly. It's very exciting.

Dr Fuster: I think that's going to be a big advantage. John?

Dr Chapman: Well, do excuse me, I'm a little bit the black sheep here, but we're tremendously excited in the field of dyslipidemia with the PCSK9, which we didn't discuss, Valentin, but maybe next time.

Dr Fuster: Okay. That's fair.

Dr Mack: I'll mention something that nobody else has talked about. I would have said leadless pacemaker, but Dr Cleland already took that. A trial that we didn't talk about is SERVE-HF showing that positive ventilation does not help central sleep apnea. The body is pretty smart and has Cheyne-Stokes respiration for a reason, and when you suppress that it actually hurts cardiovascular mortality. So I think that may be a big trial that comes out of this meeting.

Dr Fuster: Good. Okay, well, thank you very much. I think it was interesting, and I appreciate very much your views. There were no fights, but there was a good interaction. Thank you very much to all.

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