The Cardiology Show From ESC 2016 With Dr Valentin Fuster

Moderator: Valentin Fuster, MD, PhD; Panelists: Simon W Davies, MBBS; Laura Mauri MD, MSc; Franz H Messerli, MD; Jagmeet P Singh, MD, DPhil

Disclosures

August 31, 2016

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Editor's Note: From the European Society of Cardiology 2016 Congress in Rome, Italy, Dr Fuster highlights the DANISH trial on prophylactic ICD use in nonischemic cardiomyopathy, the SAVE trial on CPAP in patients with sleep apnea and CVD, and the ANNEXA-4 trial, which tested an investigational reversal agent for factor Xa inhibitors. PCSK9-inhibitor therapy for ESCAPE(ing) the need for apheresis in FH and intriguing preliminary data on apheresis as antianginal are also addressed, as are four "curiosities": yet more negative studies on stem cells and remote monitoring in heart failure, the first direct comparison of prasugrel and ticagrelor in ACS, and platelet-function testing for antiplatelet dosing.

Introductions

Valentin Fuster, MD, PhD: I am Valentin Fuster from New York, and I'm pleased to be in Rome for the European Society of Cardiology 2016 Congress, where lots of papers were presented. My colleagues and I are going to discuss the most interesting ones from this meeting. On my right is Laura Mauri, a professor of medicine at Harvard. I remember when she was first in this program, she was assistant professor, so she's following an accelerated academic career. I was asking her what is next.

Laura Mauri, MD, MSc: We'll see, maybe we can talk.

Dr Fuster: Congratulations. Next to Laura is Franz Messerli, whom I know very well, since he's professor at the Icahn School of Medicine in Mount Sinai, New York, and at the same time, he's at the University of Bern in Switzerland and the Jagiellonian University in Krakow, Poland. Welcome.

Franz Messerli, MD, FACC, FACP: Thank you.

Dr Fuster: Then we have Jagmeet Singh, professor of medicine at Harvard Medical School and the associate chief of cardiology at the Massachusetts General Hospital. Congratulations.

Jagmeet Singh, MD, PhD: Thank you.

Dr Fuster: And on my left we have Prof Simon Davies, consultant interventional cardiologist at the Royal Brompton in Harefield Hospital in London. Welcome.

Simon Davies, MD: Thank you.

Dr Fuster: All right, we have a lot of work to do here. The plan is to discuss five papers that were presented at this meeting, and then we will discuss what I call four "curiosities" very briefly.

DANISH: Prophylactic ICD in Nonischemic Heart Failure

Dr Fuster: We will start with the first paper presented in the hot-line trials. This is the DANISH study; it was published in the New England Journal of Medicine[1] under the title "Defibrillator implantation in patients with nonischemic systolic heart failure." Dr Lars Køber from Copenhagen presented the paper. For patients with symptomatology of heart failure and an ejection fraction ≤35%, the implantation of a defibrillator—I wouldn't say it is mandatory—is a class 1a indication in US guidelines[2] and class 1b in European guidelines.[3] And the question is, where are the data to support that? The data are quite strong in patients with ischemic heart disease but not so strong in patients with dilated cardiomyopathy that is nonischemic cardiac failure. There are a few papers[4,5] suggesting that a defibrillator should be implanted in dilated cardiomyopathy, if you are really trying to prevent sudden death, myocardial infarction, but basically sudden death related to rhythm problems, but there are very few data about overall mortality; it depends on what you want to die from.

DANISH is a randomized control trial of over 500 patients with symptomatic systolic heart failure, ejection fraction ≤35%, and as I mentioned, not caused by coronary artery disease. These patients were randomly assigned to have an ICD implanted or to receive usual clinical care in the control group.

In both groups, 58% of patients had a CRT [device]. The primary outcome of the trial was death from any cause (where supporting data are really lacking). Sudden cardiac death and cardiovascular death were secondary outcomes, I would have thought the primary and secondary end points would have been the reverse, but basically they tried to find evidence where we don't have it.

The results after 67 months of follow-up were absolutely equal in terms of the primary end point: 21% for death of any cause in the group with ICD and 23% in the control group. Now comes the interesting part: the secondary end point of sudden cardiac death was 4% in the ICD group and 8% in the control group. That incidence is rather low I would say, for such a long follow-up.

The conclusions according to the authors in this trial: "Prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause." But sudden cardiac death was decreased as the secondary end point. Laura, what do you think? Are you surprised at this?

Dr Mauri: I think it's a very important study. The most interesting question is, should you power this kind of a study for total mortality? They powered it for a 35% reduction in total mortality, but you don't expect that an ICD is going to eliminate all causes of mortality. They actually saw a 25% reduction in cardiovascular death, and all of that was driven by a reduction in sudden cardiac death. You saw what you expected to see, and then it becomes a question of whether you have chosen the right patient population to benefit.

Prophylactic ICD and Younger Age

Dr Mauri: It's not an all-negative study, you see the positive impact of the ICD, and interestingly, they also saw this gradient of effect with younger patients seeing a greater benefit.

Dr Fuster: It's usually younger patients that get the benefit. When you look at the graph, certainly there was a significant benefit in young patients, in terms of total mortality, regardless of the cause. What do you think, Simon?

Dr Singh: It's a terrific study, and it raises many issues related not just to device therapy and heart failure but how we approach clinical trials and heart failure itself. One of the main things it says is that there was no reduction in all-cause mortality, and that is contrary to some of the earlier studies, such as SCD-HeFT[6] and the DEFINITE study,[4] which led to the guidelines for ICD therapy and nonischemic cardiomyopathy.

The interesting fact is that those studies were actually subanalyses—for example, a subanalysis of SCD-HeFT showed that in patients with nonischemic cardiomyopathy, there was an improvement in reduced mortality with ICD therapy. The difference with this study is that patients had much better medical therapy. More than 90% of patients were on beta-blockers and ACE inhibitors and a substantial proportion of these patients actually had resynchronization therapy, which was not seen in the earlier studies, so the playing field is quite different. What it goes to show is that we probably need to revisit the guidelines on a regular basis, based on the evolution of medical therapies.

Dr Fuster: You are completely correct. There is one issue, though, in this paper that is fascinating to me, if you look at the curves, they appear to be significant after 3 to 4 years and then we all die—this is biology, so the question is how do you die? I'm sure if we prolong trials more and more than we do, we are going to see this effect.

Dr Davies: Historically in trials like V-HeFT,[7] CONSENSUS,[8] and SOLVD,[9] much of the cardiac death was sudden cardiac death, and that's very much the case here, and it's a moot point whether somebody wants to die of pump failure or wants to die of sudden cardiac death. My take-home message is it's quite nice to have some data that say, I don't have to rush to put an ICD into the patient, I can stop and think about them as an individual.

Because it's not so much the expense, it's the morbidity. This was a carefully done trial, and 4% of them had a device infection; that generally means explanting. Around 6% of them had an inappropriate shock—that's far less than previously seen, but still there's a morbidity associated with that. It's quite nice that there are data to say we can stop and reassess, we don't have to rush to put in an ICD.

Dr Fuster: Many times we don't think about the false shock and other unwanted things that happen with ICDs. What do you think, Franz?

Dr Messerli: Well, my take is a simple statistical logic. Admittedly the numbers are small, but when you think about it, total mortality was the same in both groups and sudden cardiac death was reduced by 50%, so where is the excessive mortality from? What did these patients die of, since the total mortality is the same? That would be something to look at.

Dr Fuster: The answer is that these people die from old age. This is a point I would like you to comment on, the people who are younger die more of sudden cardiac sudden death than the older people. When you pool them together, there's no difference. Let's start with you, Laura, and I'll go around everyone, very quickly. I present to you a 25-year-old person with dilated cardiomyopathy, nonischemic, symptomatic, would you put a defibrillator?

Dr Lauri: Yes. My bias in the younger patients would be yes, because there are chances of noncardiac death are low.

Dr Messerli: Absolutely, yes.

Dr Singh: Most certainly.

Dr Davies: Yes.

Dr Fuster: It seems to me that although the paper overall was negative, this is a case where you have to be cautious, because in the younger individual, we should be more prone to go ahead and implant an ICD.

SAVE: CPAP for Preventing CV Events in Patients With Sleep Apnea and CVD

Dr Fuster: We are going to discuss the SAVE study.[10] It was initiated in Australia and included participants from China, Brazil, and Spain; certainly an international study about CPAP for prevention of cardiovascular events in patients with obstructive sleep apnea (OSA). This paper was presented by Dr Doug McEvoy from Adelaide in Australia. We should review what we know about OSA and cardiovascular problems.

There is no question that patients with obstructive sleep apnea experience hypoxemia at night, tachycardia, activation of the sympathetic system, hypertension, alterations of the heart rhythm, and so forth. The literature, at least the literature I have read, says that this leads to cardiovascular events. There are data to show that continuous CPAP improves hypoxemia, sympathetic activations, and so forth, but there are no data in terms of cardiovascular events.

We should consider these changes as surrogate end points. The SAVE study, published in the New England Journal of Medicine, included close to 3000 adults between 45 and 75 years of age with moderate rather than severe obstructive sleep apnea and either coronary or cerebrovascular disease—so we are dealing with a substrate of cardiovascular disease there, but with a degree of sleep apnea perhaps not as severe as we usually see.

The patients were randomized to CPAP treatment plus usual care or usual care alone, and the primary composite end point was death from cardiovascular causes—myocardial infarction, stroke, hospitalization from unstable angina, and heart failure. The secondary end points were snoring symptoms, daytime sleepiness, mood, and so forth. Most participants were men, and those assigned to CPAP spent a mean 3.3 hours on CPAP—my understanding is that you should be on CPAP for much longer.

There were good and bad, or good and neutral, findings in this study. The apnea-hypopnea index—that is the number of hypopnea events in an hour—was significantly reduced from 29 events per hour to 3.7. At least in terms of what we might call a surrogate end point, this works. The bad news is that the primary end point of cardiovascular events was not different. It was absolutely the same between the treatment groups; 17% vs 16%.

There was a significant effect on the secondary end points: the patients who had CPAP were less sleepy during the day and experienced better mood and quality of life. The conclusion as written: "Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate to severe sleep apnea and established cardiovascular disease." What do you think, Simon?

Dr Davies: These people may have had moderate cardiovascular risk, but they certainly had a lot of apnea, hypopnea events, 29 an hour is really severe sleep apnea, and it was very effective in reducing that. It's disappointing that it didn't translate into a change in outcomes. There are difficulties rolling this out, because if between 40% and 60% of patients with cardiovascular disease over the age of 50 have got a degree of sleep apnea, it's quite difficult to deploy this technology. It's a negative result that needs to be gone into in more detail, but it slightly puts the brakes on doing this.

Dr Fuster: I will say the following; when we have patients who cannot sleep at night, the last thing they are thinking about is the cardiovascular event that may happen someday. These patients are struggling, and this in part works, in terms of better quality of life. Certainly it's somewhat surprising that the cardiovascular events are neutral. What do you think, Jag?

Dr Singh: I was surprised by the outcome. I did expect that there would have been some impact on cardiovascular outcomes, if not in hard end points, at least in some arrhythmic end points, like atrial fibrillation, which is a common concomitant occurrence with obstructive sleep apnea. But again, there was no change at all. I was surprised by the absence of impact on cardiovascular outcomes. There is some impact on their daily living. The fact that they were less sleepy, the fact that their quality of life was better, they were less anxious, less depressed shows a huge positive impact of CPAP, but it is a lifestyle issue. Using this on a daily basis is a problem, and you alluded to the fact that it was used for short period of time, which probably meant it did not affect the mechanics of the sympathovagal balance changes at night appropriately to translate into a benefit in cardiovascular end points.

Dr Fuster: Another issue I did not realize before is in regard to the timing. The worst effects of sleep apnea occur after a few hours or so, yet people tend to use CPAP machines early at night and then they get tired of it at the very time when you are supposed to use it. This was a problem in this study. What do you think, Franz?

Dr Messerli: I read the paper three times because in the introduction the authors clearly state that CPAP reduces high blood pressure, reduces insulin resistance, and that it improves endothelial function. So I was looking for all these parameters in the paper, but they're not mentioned. How much did blood pressure fall—it's not mentioned, yet there was a significant stroke reduction, P<0.05, that is small, but nevertheless. And in any study where stroke falls, usually this is blood-pressure induced. Why didn't they publish the blood-pressure data? It merits a letter to the editor.

Dr Fuster: Laura, I am surprised about one thing. It's the last statement in the paper where they say something interesting: we excluded the kind of patient with very severe hypoxemia, severe sleep apnea. What worries me is that it leaves the impression that there's nothing you should do when in fact CPAP improves the patients' lifestyle, so I think we have to be very careful. What is your opinion of this?

Dr Mauri: I agree with you that the patients did so much better having been treated with CPAP in terms of their quality of life and their sleepiness the next day and fatigue. It doesn't change whether the patient should be treated, but I think to take a step back, it makes us ask: what is the biology? We know that there's this association between sleep apnea and cardiovascular events, but does it really mediate an increase in cardiovascular events, or is it just a common end point to the patients who have these characteristics?

I don't think the trial definitively tells us the answer, it's a heterogeneous group of patients, cardiovascular and cerebrovascular disease. The cerebrovascular events may be reduced, and that's a good subject for more investigation.

Dr Messerli: But do you think that the duration of the trial is long enough to see benefits, assuming it's blood-pressure induced and you lower blood pressure over 2 to 3 years by 4 or 5 mm Hg (as was seen in the meta-analyses)? Is that sufficient to show apart from the stroke reduction and reduction in coronary heart disease also? I doubt it.

Dr Singh: I can play devil's advocate and say that CPAP is positive pressure ventilation and we know that in heart-failure patients from SERVE-HF,[11] for example—different story completely, but it can alter hemodynamics to some extent. And what is that interaction? Studying the biology more carefully is important because it can have adverse impacts in certain patients.

Dr Fuster: Another issue is the patient population studied. It's high risk from a cardiovascular point of view with a number of events in a short follow-up of about 15% to 17%. Maybe you're diluting the effect of CPAP by choosing this type of patient with relatively mild obstructive apnea type of disease but very severe cardiac disease; that might overshadow the impact. I think we are all in agreement that we should not give up on CPAP for patients who are struggling.

Dr Singh: I agree.

ANNEXA-4: Andexanet Alfa for Reversing Major Bleeding Associated With Factor Xa Inhibitors

Dr Fuster: Now, this is a very interesting paper. It deals with a problem we face with new anticoagulation drugs when patients bleed: what do you do? With warfarin, we use vitamin K, but there is a lot of controversy about the new agents such as the new factor Xa inhibitors and then with the thrombin inhibitors. About 3 to 4 years ago there was lot of skepticism that we would be able to counteract bleeding with any of these agents.

We're going to discuss andexanet alfa for acute major bleeding associated with factor Xa inhibitors in the ANNEXA 4 study.[12] Stuart Connelly from McMaster University was the first author and the presenter of this paper. The question is, can you inhibit the inhibitor when we use drugs like rivaroxaban [Xarelto, Bayer/Janssen Pharmaceuticals] or apixaban [Eliquis, Bristol-Myers Squibb]? The study used a protein adexanate, which competes with the factor Xa and basically binds to it and blocks the whole process.

I remember when the drug was in development, it was very appealing. But you are always somewhat skeptical until you see the data. This was an open-label study, where 67 patients were evaluated who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor.

The drugs that these patient were on are all the ones that we know—apixaban, rivaroxaban, edoxaban [Savaysa, Lixiana, Daiichi-Sankyo], and enoxaparin—so direct and indirect inhibitors. The patients received a bolus of andexanet followed by a 2-hour infusion of the drug (I won't go into all the dosing details).

They assessed what happened over a 12-hour period, and all the patients were subsequently followed for 30 days for clinical end points. To make a long story short: the patients were on average 77 years old (ie, older patients with a tendency to bleed). Most of the bleeds were gastrointestinal or intracranial. The mean time from emergency-department arrival to bolus was about 4.8 hours. What is fascinating is that right after the bolus, 89% of the anti–factor Xa activity is decreased. It has a fast action, and this action continues over the 2 hours of the infusion and after about 12 hours, you are at baseline, so there is no need to continue giving the drug. It depends on the circumstance of the patient.

I'm somewhat surprised by the number of thrombotic events: 18%. This is not a free ride. I don't know if changing the whole clotting system contributed to these events. Laura, what do you think about the agent?

Dr Mauri: It's important to have this agent available. Regarding the thrombotic events—we don't know what they would have been in the absence of the inhibitor because these patients had life-threating bleeding and they needed to be reversed, so we can't really have a control group. We know from another study, looking at dabigatran [Pradaxa, Boehringer Ingelheim]-reversal agents[13] that the ischemic events were on par: about 10% and 18% in this one. These are sick patients, they're elderly patients, they're coming in with life-threatening bleeding and have many risk factors for thrombotic events as well, and so you're stuck. I don't know that it's a surprise that there's a high thrombotic rate; it's the nature of the patient population that we're dealing with.

Dr Fuster: Franz, you work in the field of hypertension and you see these patients too. What a change that idarucizumab for dabigatran reversal is coming onto the market and the prothrombin complex concentrate for warfarin. Now we have these agents, it's exciting, isn't it?

Dr Messerli: It certainly is exciting. But as Laura said, these are mostly elderly, very sick patients, and it's probably unethical to do a randomized trial to help to understand the prothrombotic actions. These patients have a tendency toward thrombotic events, regardless.

Dr Fuster: The mortality in the idarucizumab study was 12%, and with the prothrombin complex it was 6%, and then the thrombotic phenomena rates were 10% and 8%. We have a lot of events in these patients, and the question is, are the events independent of what we are doing or are they dependent on what we are doing? What do you think?

Dr Singh: It's the nature of the beast, it's the nature of the disease process that probably results in the events, rather than the thrombotic component from the reversal agent, though it's difficult to say that, and I don't think it's ethical to conduct that in a randomized fashion. It's a very welcome agent for all of us who use these anticoagulants and especially in the field of electrophysiology. We do all our AF ablations with patients on apixaban and rivaroxaban and we're always worried, in case we have a perforation or a tamponade, can we reverse it, and having something like this would be very advantageous.

Dr Fuster: What do you think, Simon?

Dr Davies: It's incredibly useful, and I understand why they excluded some of the highest-risk patients. They excluded people who might need surgery within 12 hours, they also excluded people with very large intracranial bleeds—either a high volume on a CT scan, or the Glasgow Coma Scale was very low, a GCS score of 7 means they're just completely out. But for me, those are the patients in whom I most want to use this agent. It'll be very valuable in somebody who needs surgery within 12 hours or somebody with a huge intracranial bleed—they have even more to gain from prompt reversal. The anti–factor Xa activity was unmeasurable within minutes of the start of the infusions.

Dr Fuster: Laura, when do you think we will have all these investigational agents available to us? Certainly, we have the prothrombin complex concentrate (four-factor PCC) available for warfarin reversal.

Dr Mauri: It depends on the country, but we have the dabigatran reversal agent in the US, and many countries allow compassionate use.

Dr Fuster: It's not easy to get approval. If you have a patient who bleeds and you want to use it, good luck.

Dr Mauri: Fortunately, these are rare. Regarding the risk of the agents vs the risk of the situation, we don't have enough information to use these agents on an everyday basis for minor procedures. They're really only for these extreme circumstances.

Dr Fuster: But it is a great relief that it is becoming available.

Dr Messerli: Do we know anything about the cost? That is another issue.

Dr Fuster: If you have a major bleed, it may only be once in your life.

Dr Messerli: That is true.

Apheresis in Patients With Angina and High Lp(a)

Dr Fuster: You are right, these are very expensive. Now I'd like to touch on two papers that I think are interesting. Both are on plasmapheresis. The first paper is on patients who have angina and high Lp(a).[14] Lipoprotein (a) is becoming more important in our practice. We see a number of young people, and the only risk factor they have is a very high Lp(a). These patients have thrombotic phenomena regardless of the mechanism (which we are not going to get into). The researchers propose that the viscosity of the blood in these patients may cause angina and ask if you could reduce the Lp(a) and the angina with plasmapheresis. I wouldn't say that it disappeared in their study, but it certainly improved significantly. This paper was presented by Dr Tina Khan from London. It's interesting to make a connection between refractory angina and levels of LP(a). Frankly, this is new to me, but it makes sense. We have seen people with high red-cell counts. I was not aware of the Lp(a) connection; this is only a hypothesis, but it seems to me that this it is real.

The purpose of this study was to see if reducing the level of Lp(a) (which was >500 mg/L) would improve myocardial perfusion as quantified by magnetic resonance imaging. The number of patients was very small, only 20, and this was a crossover study, so everyone experienced both approaches with plasmapheresis and without over 3 to 6 months. The results are certainly very informative. They had a significant improvement in the quantitative perfusion observed by magnetic resonance imaging and an improvement in exercise capacity, angina symptoms, quality of life—I have to see those data. They also said that you get less carotid atheroma. I think that may be a stretch, because it wasn't in the presentation, so I cannot judge. What do you think about this, Jag, had you heard of this before?

Dr Singh: No, I am hearing about it for the first time. It's fascinating to think that just removing the Lp(a) can change the atherosclerotic process. The question that comes to my mind is how long do you continue doing it, because after you stop apheresis, the likelihood of Lp(a) increasing again is quite high. Then you would have your refractory angina and the atheroma all recircling again. Does it translate into better long-term outcomes so you can see that there are physiological changes, and how often do you have to repeat it? Those would be very interesting questions to answer in the future.

Dr Fuster: I think you are completely correct. However, we have some experience in familial hypercholesterolemia, where patients get used to plasmapheresis every 2 weeks or so, and in general these are young people. I'm very impressed by their resilience to undergo plasmapheresis, not for LP(a), but for LDL cholesterol. Perhaps if we learn more about the risks of high Lp(a) people will become used to plasmapheresis for that too. What do you think, Simon?

Dr Davies: Like you, I didn't know much about this, but I seem to remember from my studies in primary infarction that Lp(a) is a really a strange particle. It's a splicing of the genes for plasminogen and apolipoprotein B.

Dr Fuster: It competes with the plasminogen activator, so you may have prothrombotic phenomena.

Dr Davies: I gather it's arisen twice in evolution, once in primates and once in hedgehogs. We don't do apheresis in many hedgehogs, but there are a lot of primates that might need it. We've all seen small studies with very, very positive results; this had only 20 patients. What impressed me was that it was a crossover study, and they actually did sham apheresis in the control group.

Dr Fuster: Yes, they did.

Dr Davies: It was a fairly carefully conducted study, and if the magnetic resonance imaging was analyzed blind, there might well something in this.

Dr Fuster: So what do you think, Franz?

Dr Messerli: When you reduce viscosity, according to Poiseuille's law, this should have hemodynamic repercussions. I would like to know what happens to total peripheral resistance, blood pressure, and so on. They did not look at that. There are not only prothrombotic effects, there should also be some hemodynamic effects.

Dr Fuster: Laura, we have patients with high Lp(a), and we don't know what to do, but this is an interesting approach.

Dr Mauri: As you point out there are two potential pathways being influenced, one may be viscosity, the other prothrombotic. This study looks at mainly at the viscosity issue through a surrogate end point, the cardiac MR. I think it's very interesting. I'd like to see the next study before we can really understand the mechanism and see if there is an impact on events.

Dr Fuster: In the past, the two mechanisms past have been 1) competition with plasminogen activator—ie, prothrombotic—and 2) doing the same as LDL-C via atherogenesis. At least there is some hope for the Lp(a) problems that we face from time to time.

ESCAPE: PSCK9 Inhibitor to Reduce Apheresis Frequency in HeFH Patients

Dr Fuster: Now we are going to get into the ODYSSEY-ESCAPE study.[15] The title of this study was "The effect of alirocumab on the frequency of lipoprotein apheresis. A randomized phase 3 trial." There were 14 study sites in Germany, and this was presented by Dr Patrick Moriarty.

We all know families with familial hypercholesterolemia; it occurs in about one in 200 people, maybe more when you do proper genetic analysis. What do you do? These are young people, and you can try to lower the LDL-C with statins and so forth, and you always fall short. You cannot really get in down to the levels you would like. Many of these people have terrible family histories, and they undergo plasmapheresis. The question that this study addresses is whether the new PCSK9 inhibitor such as alirocumab [Praluent, Sanofi/ Regeneron] can reduce the need for apheresis. Can we escape it? I assume that is why this is called the ESCAPE study. They gave alirocumab 150 mg every 2 weeks, and the results were very significant. It was an 18-week study, and apheresis time could be reduced by 75% vs placebo in these individuals by just giving this continuous alirocumab. Apheresis was completely discontinued in 63% of the patients.

I have treated a few patients like this, and we could not discontinue apheresis completely, but there was no need to do it every week or every 2 weeks. You can lower the LDL cholesterol significantly, so I think this is exciting. What do you think?

Dr Mauri: It's amazing. We couldn't have even thought of this years ago, and now to have something that may eliminate apheresis, even if it is in a very well-defined patient population. I think it's very important.

Dr Fuster: This is exciting. Franz?

Dr Messerli: No question it's exciting. But I'm a bit concerned that these are young patients, and they will be treated for years. The safety of the treatment long term still carries a question mark. They only have very short-term data, and there are some hints there could be some cerebral effects with these drugs that are not necessarily positive. We have to be very, very careful here.

Dr Fuster: You make a good point, but these people are very sick. I have two patients, women in their 30s, who already have had aortic-valve replacement. We are dealing with cholesterol levels that are very high—LDL-C above 200 mg/dL (5.2 mmol/L). We have to follow these drugs carefully. What do you think, Jag?

Dr Singh: I think it's fantastic that there is an alternative agent now, which can avoid an invasive therapy like apheresis. But I have the same concerns as Franz, and it's important that we show that this actually impacts outcomes, because apheresis does have other pleiotropic effects. It has antithrombotic effects, anti-inflammatory effects, which may not necessarily be there with PCSK9 inhibitors. Looking at long-term outcomes is going to be important.

Dr Davies: I agree. We have homozygous FH patients with very high pretreatment cholesterol levels of 20 mmol/L [770 mg/dL] in our units. It's very hard to get them to target, and if we can reduce the frequency of apheresis from every week to once a month for the young patients, that would be beneficial. I know alirocumab is a humanized monoclonal antibody to PCSK9, but self-injecting a foreign protein frequently over years—I wonder will there be some resistance, some kind of reaction to it? At the moment, it's very encouraging.

Dr Fuster: We didn't think we'd see something like this 5 years ago, but we have to be cautious.

CHART-1: Cardiopoietic Regenerative Therapy (Stem Cells) in Heart Failure

Dr Fuster: Now, we will go into four curiosities. The first is on mesenchymal cells. Stem cells are not one of the highest priorities today among those of us who deal with elderly patients with heart failure. Bone-marrow cells have been used in thousands of trials with not much success.

In the past few years, mesenchymal cells have been considered the best progenitor cells because they can be transformed and have better embryogenic effect. The largest study ever done with mesenchymal cells—actually it's also the first one—is the CHART-1 study.[16] Jozef Bartunek from Belgium presented this study, the title is "Congestive heart failure, cardiopoietic regenerative therapy: Clinical trial primary outcomes."

It included more than 62 patients with advanced ischemic heart failure, ejection fraction <35%, highly symptomatic, and 12 months of follow-up after a number of injections of stem cells, and the primary efficacy end point included the usual clinical end points. And the results were negative; same for hemodynamics, ejection fraction, and so forth, negative.

They did a subanalysis in a subpopulation defined by the degree of LV dilation and still saw nothing. There are other options of cells to use and I think the field will continue, but as far as bone-marrow cells and mesenchymal cells, things do not appear to be exciting. Simon, what is your take?

Dr Davies: The message, as you say, was overall negative. It was a very well-conducted study. They even did sham injections without stem cells. I think their subgroup analysis seemed to be straining a little bit.

Dr Fuster: A little bit?

Dr Davies: They talked about treatment intensity. It looked slightly better in the people who had more than 19 injection locations, rather than less, and, as you say, the people with larger ventricles. But even that didn't achieve statistical significance at the conventional level.

Dr Singh: I'm pretty lukewarm, having injected stem cells myself in many hearts. Most of the studies have been neutral or negative. We still don't know the best type of cell, how to administer it, the best way to target it, or the best retention strategies. I'm still waiting.

Dr Fuster: Maybe a combination of cells and cytokines. I am quite excited about the genetic induction approach. There are studies beginning to evolve in Japan, China, Singapore, working on retinal disease, and they are already doing that. It's quite fascinating. When you do this in vitro, you get mutations, and this is why human studies have not been advancing so rapidly. But if you do it directly, you may bypass many of the processes that cause mutations or oncogenesis. I say this because I don't want to leave the impression that this field of research is a fiasco. All we are saying is the injection of cells from bone marrow appears to be negative. What do you think, Laura?

Dr Mauri: It's challenging. It's interesting that you raised some areas outside of the heart where there might be more direct visualization of the transplanted cells, so that we could perhaps understand function better. I'm not a basic scientist, but there's still so many questions about the best type of cell.

Dr Fuster: Franz?

Dr Messerli: Question to Jag, given what Valentin said that there are hundreds, if not thousands of studies with stem cells that have been by and large negative. This study is not very positive either. Should we abandon this line of research for the heart? For other tissues, maybe it's a different story.

Dr Singh: No, I wouldn't abandon it. This is an area that certainly needs a lot more work, a lot more innovative thinking, and maybe, as Dr Fuster said, working locally to create some changes there. With the current strategy, whether you use intramyocardial injection or intracoronary injections, the retention of the stem cells is literally not there. And then we have this whole pleiotropic effect and trophic hormone effect that we keep ascribing changes to, but the results have been, as I said, fairly lukewarm, and not very exciting.

Dr Fuster: I'm hopeful about understanding the genetics better, but certainly the cell therapy is not working.

ANTARCTIC: Platelet-Function Testing to Tailor Prasugrel Dose in Elderly Patients With ACS

Dr Fuster: Previously, we talked a lot about platelet function and genetic studies in patients undergoing PCI with clopidogrel treatment to assess resistance to clopidogrel. This has been falling apart. If you have a complex patient, you don't look at the platelet function. Here we have the ANTARCTIC study[17] led by Prof Montalescot, who was very involved with this line of research. Most of the patients were on prasugrel [Effient, Lilly/Daiichi Sankyo] following PCI, and the question is, do you need 5 mg or do you give 10 mg? They did platelet-function tests to decide, and the results were negative. Laura, this is very close to your heart. What do you think?

Dr Mauri: This negative study was very well done—an attempt to better personalize medicines specifically in elderly patients with ACS. It had a clever design to reduce the dose in patients who had too much of an impact from prasugrel and increase it in other patients. The aim was to really personalize the treatment. They looked to this combination of bleeding and ischemic end points and saw no difference in any of the components.

Dr Fuster: The patients were over 75 years of age, so these were people at risk of both thrombotic and bleeding events.

Dr Mauri: That's right. It's the most challenging patient population that we face for balancing these two things. We know that age is the most important predictor of bleeding, so the take-home is that we don't have a great reason to use platelet-function testing in practice. We have so many important clinical predictors that we can use.

Dr Fuster: These are clinical judgments. We all have a formula in our heads, and there's a lot of common sense in how to approach these patients. I don't think we have to discuss this any further.

PRAGUE-18: Ticagrelor vs Prasugrel in Patients Undergoing Primary PCI

Dr Fuster: Let's go into the next curiosity: the PRAGUE-18 study[18] comparing ticagrelor [Brilinta, Brilique, Possia, AstraZeneca] vs prasugrel in patients with ACS. It had a short follow-up of about 30 days. In this study done in the Czech Republic, over 1000 patients were randomized following an MI and PCI, and the primary end point was death, infarction, revascularization, stroke, serious bleeding. The results were the same, 4.0% vs 4.1% in the treatment groups.

I'm not sure if the study was too short. What do you think about it?

Dr Singh: It's like a noninferiority study. Maybe we didn't see any differences between the two groups because the sample size was not large enough and the follow-up was not long enough. From what I understand as an electrophysiologist, the mechanism of action for these drugs are almost identical, and they seem to be pretty identical in their effect.

Dr Fuster: Are you surprised, Laura?

Dr Mauri: I'm not surprised by the study outcome. The reason they did this study is because ticagrelor has shown a reduction in mortality compared with clopidogrel[19] in patients with MI, and prasugrel has not.[20] You can't compare across trials, so this is an attempt to compare ticagrelor with prasugrel. The study wasn't designed as a noninferiority study. It was not powered to say that they were equivalent outcomes. The best you can say is that with the sample size they had where the power was limited, they didn't see a difference.

Dr Fuster: And the short follow-up.

Dr Mauri: I think they're going out to 1 year, so maybe we will see more. But there are some limitations with the design as well that make me concerned that even if we see no difference at a year, that there still may be a real difference between the two. We don't know. Patients were allowed to switch to clopidogrel as soon as they were discharged.

Dr Fuster: Franz, one concern I have with these paper is why this is probably so premature. You know, they are going to go into 1 year.

Dr Messerli: They state they will have the final data May next year. They should wait because it doesn't help us much. The data as they are now are provocative, but they don't help us to treat patients, so why don't we wait until we have the final data before we make any judgments?

Dr Singh: It was prematurely terminated because of futility. They found that there was not much difference between the two arms. But I think a part of that was the sample size.

Dr Fuster: Maybe they stopped the recruitment.

Dr Singh: They were going to recruit about 2000 patients, and they stopped it at 1200 or so.

REM-HF and MORE-HF: Remote Monitoring in Heart Failure

Dr Fuster: Let's see the final curiosity. There were two studies presented about the assessment of defibrillators remotely in a wireless way. You can do this at home to see how you are doing or you can go to the hospital or to the doctor's office. The first study is REM-HF, a British randomized study of 1500 patients.[21] They looked at primary end points, hard end points, and also how many people had to go to the hospital to be checked because things were unclear with the remote monitoring. They found no difference at all. Remote monitoring didn't make a difference.

The second study from Italy was the MORE-CARE study published in the European Journal of Heart Failure.[22] It had a very similar design, 900 patients, and the results were very similar. No difference in outcomes with remote monitoring with one exception: the remote-monitoring group didn't go to the doctor's office or talk to them [on the phone] as much as the group that was checked in the hospital or the physician's office. The whole thing looks negative. But if I had a defibrillator, I'd prefer to be checking it at home. Wouldn't you? There may be no differences in cardiovascular events, but in terms of convenience, I would think that being able to check it at home is an advantage.

Dr Davies: I agree. There are parallels: we know with anticoagulant monitoring the patients who have CoaguChek at home can't resist doing it every week, and as a result their INRs are very well controlled. In heart failure where we have ambulatory-care nurses, we know that simple clinical rules prevent admissions. The results are slightly disappointing because with this very high-tech gizmo, you would've thought that interrogating the logs and tuning the device accordingly would have achieved something. Maybe these devices are so good. It may be like some of the other trials we've talked about, where the medical therapy is so good (everyone's on ACE inhibitor, a beta-blocker, on a mineralocortoid antagonist) that the event rate just wasn't high enough to see an effect. They were already optimally treated.

Dr Fuster: Jag, what do you think?

Dr Singh: The results are counterintuitive. I would have guessed that remote monitoring would help in many ways. It certainly can reduce the outpatient visits by not having to bring the patient in to check their devices. Second, it could detect any fault with the device or with the lead system early on. That's just the device itself. Obviously remote monitoring for reducing heart-failure hospitalization is a different entity, and for that you really need to have the appropriate infrastructure to make sure that there's an appropriate transfer of information between the electrophysiologist, the heart-failure doc, and the remote monitoring center. I'm not so sure that they tested that specifically in an integrated way.

The Panelists' Top Picks and Closure

Dr Fuster: We are going to finish, and I am going to ask each of you to pick the most important study among everything we discussed. Franz, you are the first.

Dr Messerli: I liked the sleep-apnea study, the CPAP study. I was fascinated by the results, but nevertheless I would like to see a little bit more details with the surrogate end points that they completely forgot about. A provocative study, but not the way it should be.

Dr Fuster: But you liked the study? I want to be very sure.

Dr Messerli: I liked the study.

Dr Fuster: Laura?

Dr Mauri: I really liked the DANISH study. Even though on face value it's a negative study, there's a lot of information that will be important to follow up on because there is a subpopulation that's going to benefit.

Dr Fuster: Thank you. Simon?

Dr Davies: Also the DANISH study. It tells us not to rush to put an implantable device into somebody with low ejection fraction that's nonischemic, but to think carefully about the younger patients.

Dr Fuster: Jag?

Dr Singh: I like the DANISH study for two reasons. It brings up the fact that we should question the quality of evidence on a regular basis. Second, we learned that we need to individualize our treatment strategies in patients, be it by age or comorbidities.

Dr Fuster: What I liked the most were my guests. This is a very interesting group. It's not that we were in total agreement. There has been a lot of judgment. We've had many of these sessions, and sometimes there are fights, which is interesting. But I get the sense of a consensus about all the studies that we discussed, and this is comforting. Thank you very much to the four of you. I hope to see you soon again.

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