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Editor's Note: Dr Fuster chose to see the glass half full at this year's European Society of Cardiology 2014 Congress and picked positive trials to discuss with Drs Chapman, Moat, Mehran, O'Donoghue, and Singh. These included PARADIGM HF, showing a potential breakthrough for heart failure with LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), and the ODYSSEY trials on alirocumab, the first PCSK9 inhibitor to show not only a reduction in cholesterol levels but also clinical events. However, drug therapies are effective only if patients take them; the show ends on the sobering note of poor medication adherence.
Valentin Fuster, MD: I am Valentin Fuster from New York, and it is a pleasure to be in my native city Barcelona at the European Congress of 2014 Cardiology. I feel at home and very relaxed; it's like playing soccer with the home-field advantage. I am joined by a very good group of colleagues; London, Paris, New York, Boston are represented. Let's introduce you. On my left Prof John Chapman, former president of the European Atherosclerosis Society, who works at the Pitié-Salpétrière University Hospital in Paris, and director of INSERM. Thank you very much for coming.
M John Chapman, PhD, DSc: Pleasure.
Dr Fuster: We have a surgeon Neil Moat, who has a title of cardiologist. He's the director of the transcatheter valve program at the Royal Brompton Hospital in London. Welcome.
Neil E Moat, MBBS: Morning.
Dr Fuster: Roxana Mehran, I see her every day when she's not traveling. She is a professor of medicine at Mount Sinai School of Medicine in New York. Thanks for coming, Roxana. Here on my right is Dr Jagmeet Singh from the Massachusetts General Hospital, Harvard Medical School, and he is really an expert on arrhythmias. He runs the cardiac arrhythmia service. Finally on my right, Dr Michelle O'Donoghue, who's an associate physician at the Brigham and Women's Hospital, and she covers every field, so between us all, we should be able to answer any question.
There is one problem at this meeting; the glass is half-full, half-empty. The problem is that 75% to 80% of the studies presented were negative, with negative results, which makes us wonder about what is going on here. On the other hand, about 20% were positive, and we are going to focus on the positive trials. We are going to discuss five studies that touch different fields: cardiac failure, acute coronary syndrome/acute myocardial infarction, chronic coronary artery disease, and finally we will address medical therapies with a study showing a breakthrough in the lipid field, and another on the polypill in secondary prevention. I think we are covering five interesting fields and I appreciate the panel being here this morning.
PARADIGM HF Angiotensin Receptor Neprilysin Inhibitor vs Enalapril
We are going to start with cardiac failure and the PARADIGM-HF study. Everybody at this meeting is talking about this study, so I had to go into detail last night to be sure that I pronounce things properly. The study was just published in the New England Journal of Medicine[1] and the first author is John McMurray from Glasgow, and the presenter of this trial at the ESC meeting was an old colleague of mine, Dr Milton Packer, who is now in Dallas.
This is a fascinating international study and we should give some background. It's interesting to follow the field of cardiac failure over the past 20 years. I still recall the first trials on ACE inhibitors, angiotensin-receptor blockers, then beta-blockers, then mineralocorticoid steroids, receptor blockers, but now we have something new, neprilysin (maybe the surgeon can tell us how it works later).
Dr Moat: Exactly.
Dr Fuster: Neprilysin basically leads to vasoconstriction. In the area of cardiac failure we have to vasodilate, so this drug includes the neprilysin inhibitor sacubitril. Actually the study compared a conventional ACE inhibitor, enalapril, with LCZ696 which is a combination of two drugs, the angiotensin-receptor blocker valsartan and sacubitril.
The study included over 8000 patients with New York Heart Association class 2–3 and class 4 heart failure, with a low ejection fraction (≤ 40%). They received the investigational drug LCZ696 or enalapril. The enalapril dose was 10 mg twice a day and LCZ696 (the combination drug) dose was 200 mg twice a day. The dosing is important because a study[2] of another neprilysin inhibitor vs enalapril used once-a-day dosing and there were some problems, so it's a drug that you have to give twice a day.
The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. And they also looked at all-cause mortality. The follow-up was 27 months, and the results were spectacular. Regardless of which end point you look at, there was over a 20% reduction. For example a 20% reduction in cardiovascular death, a 20% reduction in the primary end point, and a more-or-less 20% reduction in heart-failure hospitalization. This is quite surprising, because as Roxana was mentioning earlier, we had already decreased it by 20% with ACE inhibitors, and now the ACE inhibitor is the control arm, and we see a further reduction of 20%.
Michelle, what is your reaction to such a study?
Michelle O'Donoghue, MD: Of all the conferences I've been to in the last several years, I've never heard more excitement over the results of a clinical trial than this one. I think it's very appropriate, I mean we're talking about an innovative new therapy that appears to have both a mortality reduction as well as a reduction in hard cardiovascular events for patients with heart failure. The trial name is PARADIGM, which is appropriate because this is a paradigm shift in how we might treat our patients as we move forward.
Dr Fuster: It's interesting that we have more and more cardiac failure as the population gets older and older, and you're going to see more and more arrhythmias. Do you think that this type of treatment in cardiac failure is going to decrease the incidence of arrhythmias? We don't have data, but what do you think?
Jagmeet Singh, MD: I think that when there is a reduction in overall cardiovascular death, a part of that could be through a reduction of arrhythmia, so one could certainly speculate that there may be some beneficial effect in reducing arrhythmias. It does change the playing field quite a bit, because if you look at it from the electrophysiologic perspective, routine device therapy requires that patients be on optimal medical therapy. Now, is that optimal medical therapy going to change in that they need to be on an angiotensin-receptor/neprilysin inhibitor (ARNI) instead of an ACE inhibitor? That is one question. Another question is whether we are going to start replacing ACE inhibitors with ARNIs, and do we have the resources to suddenly bring about the switch?
Dr Fuster: That's a very good point. Roxana, what do you take from this study?
Roxana Mehran, MD: This is really groundbreaking for heart failure, and it's about time for some excitement in the field of heart failure. But whenever a trial is stopped early one, always wants to take in all the information (but let's not take away from the enthusiasm for this important innovative therapy). I also want to point out that the "placebo" that we had back in the days of comparing ACE inhibitors with placebo is very different from today's standard of care with beta-blockers and aldosterone inhibitors. We have seen so much improvement in our baseline therapies, so I think that 40% reduction is most likely a little bit inflated, but that aside, this truly is a paradigm shift and it's very exciting.
Dr Fuster: John, what do you think?
Dr Chapman: If we situate this therapeutic advance in the context of the dramatically changing demography around the world and the enormous increase in cardiac insufficiency and heart failure, then this really is potentially a major advance.
Dr Fuster: Neil?
Dr Moat: The other positive thing is the patients' symptoms seemed to improve and their quality of life got better, so it's not just they're living longer, they're actually having a better quality of life, which is an important feature as well.
Dr Fuster: We talked previously about the cause of death, but we don't have that information in the paper.
Dr Singh: Right. There are no details about whether arrhythmic death was seen or not. But one could speculate that there probably could be. One question not addressed that is very important from the electrophysiologist's perspective is "was there remodeling?" Is there a reduction in the ejection fraction, or is it just a symptomatic benefit and overall a milieu benefit that they're getting? That's something that needs to be teased out, because if there is remodeling and there is improvement in ejection fraction, that again is going to affect the way we approach these patients for device therapy and also how we risk-stratify them in the future.
Dr Fuster: Michelle, we were talking before the taping about the mechanism of this drug. You made a comment that this is an enzyme that degrades certain vasodilators. Is that correct?
Dr O'Donoghue: Right. The mechanism of action to some extent is still being teased out as to which mediators are perhaps offering the more therapeutic benefit. But in essence, this drug is an endopeptidase inhibitor, and we know that substances such as natriuretic peptides are degraded by endopeptidases, so by blocking that enzyme you're going to cause natriuretic-peptide levels to rise as well as other substances such as bradykinins. Which one of those is responsible for the benefit of this drug? I think that that's something that obviously people are very interested in, because some of the prior compounds have led to different fluctuations in different mediators, so it would be interesting to find out.
Dr Fuster: I bring up vasodilatation because one of the problems with the drug previously was acute laryngeal edema, and this is thought to be due to vasodilatation, but that was not a significant problem in this study. There are some issues about the side effects. The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema, but lower proportions of renal impairment, hyperkalemia, and cough compared with the enalapril group. There are some side effects we have to be careful about, and we will learn more in the future.
I think we touched the critical issues of this study. I think it's very exciting. The number of patients is significant. And although the study was stopped prematurely, this was all prespecified that when a certain end point was reached, the study would have stopped. It was not stopped because something happened that was not predicted, and I think this in a way at least solves intellectually some of the questions that people might have.
Dr O'Donoghue: Absolutely.
CVLPRIT: Complete vs Lesion-Only Primary PCI
Dr Fuster: Okay. Let's then move into other excitements. We are going to be talking about the CVLPRIT trial.[3] This is a study on managing multivessel disease during primary PCI in patients with STEMI. The background is the PRAMI study[4] which asked whether we should perform PCI in the culprit lesion and then eventually take care of the other lesions or do all the lesions at one time. As I recall, the results were significantly in favor of doing all lesions at the same time (Roxana can correct me if I'm wrong), But the patients were not at very high risk in the PRAMI trial, which made me question whether it would be the same story in acute myocardial infarction. Am I correct?
Dr Mehran: Yes, the background to this study is the PRAMI study, and as you point out, one of the issues with the PRAMI study was that the criteria to randomize patients to either complete revascularization vs leaving it alone was not standardized. We didn't know who those patients were and we couldn't really translate it to the real world.
Dr Fuster: It took a long time to get a relatively low number of patients.
Dr Mehran: That's right, 465 patients in five years.
Dr Fuster: Okay, but are we going to get the answer with CVLPRIT? It's a similar study, the complete vs lesion-only primary PCI trial. This was presented by a British group by Dr Anthony Gershlick from the University Hospitals of Leicester. The number of patients was relatively small, 236 patients with STEMI and multivessel disease. How many patients did PRAMI have?
Dr Mehran: Four hundred and sixty-five.
Dr Fuster: So about half again: 236 patients. The randomization was to infarct-related artery only vs complete revascularization. The stratification randomization took into effect the site of the infarct as well as the symptom-onset-to-balloon time. Interestingly the primary end point was MACE at 12 months, comprising total mortality, recurrent MI, heart failure, and ischemia-driven revascularization.
The results are impressive, but the number of patients is small. Let's see what we can make of it. There was a 55% reduction of MACE. If you did the procedure at the same hospitalization it went from 12% to 5%; a very significant reduction of events. But how do you react to a study like this when you are dealing with close to 200 patients, do you make a big deal of it?
Dr O'Donoghue: No, and I think that you and Roxana have raised this point. We have PRAMI and we now have the CVLPRIT trial; both are relatively small, but at the same time it does give you pause when the results are really consistent between the two studies. Even the hazard ratios are very consistent between the two trials. It does raise into question whether or not we should be treating nonculprit arteries during the same hospitalization. I'd be interested to see if any of you already changed your clinical practice based on PRAMI or whether you're waiting for more data.
Dr Fuster: Roxana, you're the head of clinical trials and interventional research at Mount Sinai, we talk about these things all the time. Give us your reaction to this study.
Dr Mehran: I think it's an extremely important question and a dilemma that we face all the time. What do we do with that 90% lesion in the other artery? And how comfortable do you feel leaving it alone? We're going to talk about FAME and [fractional flow reserve] FFR later, but it really is something that interventionalists think about all the time. Please note that performing the intervention in the nonculprit vessel is a class III indication in the ACC/AHA guidelines [ie, no benefit or potential harm].
Dr Fuster: Right.
Dr Mehran: There's a clear recommendation not to move forward and that is based on meta-analyses of registries. Then for the first time and now for a second time we have data saying it's okay to move ahead—in fact, you might improve outcomes. But we still have to take a step back because if you put together all of the events in PRAMI as well as CVLPRIT, you have a total of 100 events, and with just one or two movements in the other different direction, things could change. That's the dilemma. Should that class III indication change to at least give physicians some room to move forward given these two trials?
Dr Fuster: Get rid of the class III?
Dr Mehran: Get rid of the class III, and give it maybe a class IIb or what have you, and continue to enroll in the study that is best suited to answer the question, and that is the ongoing COMPLETE trial, with 4000 patients. It is not testing full revascularization in the same setting—it compares staged vs wait and see. That's Shamir Mehta's study, and it's a very important question.
Dr Fuster: Neil.
Dr Moat: What Roxana says is true, it is a very important question. There were a couple of interesting features of the CVLPRIT trial: the complete revascularization was not always performed at the same time. The design was to perform it during the same hospital admission. That's relevant, because if you look at the difference that occurs, it seems to be there by 30 days, so a lot of the benefit occurred very early. That raises the question, should these lesions be treated simultaneously or at most the very next day because you may be losing any benefit if you leave it for a week or two? It's a small study, it tends to support PRAMI, but I agree we need a lot more patients before we can say that this is absolutely the right way to go.
Dr Fuster: But at least both studies make us think, is that right, John?
Dr Chapman: Well, they do. What concerns me about studies like this is that atherosclerosis, as we are very well aware, is a diffuse disease in the coronary tree. From the work of people like yourself, Valentin, we know that plaques can be vulnerable one day but not the next. In a sense I think if we think about the dynamics of plaques and stability vs instability, then really how can we possibly think that we should restrict ourselves to the culprit plaque and "ignore" (if I can say that in inverted commas), the diffuse nature of this disease, particularly in these very high-risk individuals in whom the probability for a recurrent event in the 30 days after that index event is enormous. I'm concerned here that this could put us on a potentially false therapeutic track, if you will.
Dr Fuster: What you are saying is that the disease is complex, and we are dealing with anatomy, and it is much more difficult. At least in this case, what you do is you delay, you don't ignore. You delay the process, but you take care of everything. This will lead to the next study we're going to discuss, which is FAME-2, which begins to touch on the risk of different lesions, not necessarily vulnerability. Do you have any comment about this, Jag?
Dr Singh: As an electrophysiologist, I would say that after an MI the patient is at highest risk for an arrhythmic event in the first month or so. If you're intervening on other vessels that are critical, you're actually modifying the substrate favorably. I don't know how many of these events were arrhythmic, but clearly the separation in the curves is very early. It was actually during the hospitalization itself when the curves separated out. I find it very intriguing, and I'm leaning toward the results changing practice or at least influencing it because remodeling the substrate early may actually translate into better outcomes.
Dr Fuster: Michelle, is this fair to say that we should remove the class III?
Dr O'Donoghue: I agree that it is probably premature for everyone to change practice, but in my mind it raises two interesting questions. One is whether this is something that's specific to the STEMI disease state. Of course acute inflammation is going to exist for patients with non-STEMI as well, so is this really unique to our STEMI population? Should there be trials or should we be thinking about whether or not to intervene on nonculprit lesions in the non-STEMI patients as well? That's one thing that gives me some pause. The second is the question of plaque vulnerability and how to assess that as we prepare to talk about FAME-2. For CVLPRIT, they based their decision on the percent stenosis. But I think we have some understanding that perhaps in the ACS state that the degree of inflammation is really what's going to be predicting benefit, and how do we assess that?
FAME-2: FFR-Guided PCI vs Medical Therapy Alone
Dr Fuster: As John said, it is complex. Let's make things simple. I'm not sure, but we will try with the FAME-2 study.
We are now moving from acute coronary disease to stable coronary disease. The thing that bothers me about stable coronary disease practice is that 50% of the patients who undergo procedures don't have a stress test. It bothers me because we are now going to talk about the "stress test" that you do in the cath lab. My question is, why didn't we do it [a regular stress test] before? Just to put things in perspective. It seems to me we are going too far and we can't see the forest for the trees. Anyway, the FAME studies were fantastically done.
This is FAME-2, which we already had some results from.[5] The latest paper just came out from the New England Journal of Medicine, and the first author presented this yesterday. Dr Bernard De Bruyne from Aalst, Belgium. He has been the driving force of the FAME studies. The studies include European centers, academic centers, and centers from North America.
First of all FAME-1 [6] (maybe Roxana you will correct me) showed that if the ratio of the gradient after vasodilatation is above 0.8, don't use PCI, and that was very clear. The question asked with FAME-2 was, What do we do when this ratio is 0.8 or less? The results, at least the short-term results, suggest that revascularization is better—ie, you do PCI, but there was no change in the hard end points like mortality, myocardial infarction, by doing PCI on these stable patients with a low ratio.
Now we get longer follow-up, and my worry with this paper is that it is like a long-term ad hoc analysis of what happened after, and we will discuss in a moment whether this was prespecified or not. But first let's go into this study.
It included over 1000 patients with stable coronary disease who underwent FFR assessment of all stenoses visible on angiography. If the FFR was 0.80 or less they were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. They used second-generation drug-eluting stents, which is important to note. Patients in whom all stenoses had an FFR of more than 0.8 followed the FAME-1 protocol and were treated medically and entered in a registry. Now the primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within two years.
The results of the regional study: the rate of the primary end points was significantly lower in the PCI group than in the medical-therapy group, and I repeat this was a ratio of 0.8 or less. In terms of end points, the rates were 8.1% in this group with PCI vs 19.5% in the group treated only medically, despite the low ratio. The key issue is that when you look at the three components of the primary end point, the only one that is significantly reduced is revascularization.
Then comes the second part of this study, which is what happened at two years, and now we see a reduction in mortality and myocardial infarction in the patients that were treated with PCI vs those who were treated medically. The overall message of the paper is when we face patients with a stable coronary artery disease, FFR-guided PCI as compared with medical therapy alone improves the outcome by following the rules of the ratios that we mentioned.
And again, my question is whether this was prespecified or whether this is ad hoc. I'm a little bit worried about it. What do you think, Roxana?
Dr Mehran: I think this is a really important study and a response in some ways to the COURAGE [7] study, which basically said that in stable angina, an initial strategy of medical therapy is just fine and that there's no benefit from PCI in terms of a reduction of death and MI. FAME-2 was set up to assess ischemia-driven revascularization. If there is ischemia (assessed by FFR) the patients who have ischemia probably would benefit from PCI compared with medical therapy. That was actually shown in the COURAGE ischemia substudy.[8] FAME-2 aimed to show it in real life as a follow-up to FAME 1.
The issue here was that after 40% of the patients were enrolled in the trial, the trial was stopped prematurely by the [data safety and monitoring board] DSMB such that the accumulation of events (the hard end points you mentioned, death and MI) were not realized, and obviously you're underpowered for that particular end point. I think that brings us back to trials that are stopped early: how do you interpret these results? The landmark analysis had a prespecified end point and it shows a trend, that's all you can say at this point because you are not powered. But there is no question that there's some benefit.
Dr Fuster: This was after the trial was stopped they followed the patients?
Dr Mehran: It was followed all the way out to two years to accumulate more and more events. It's an extremely important study showing that when interventionalists perform ischemia-driven revascularization they are doing a good thing for their patients. But we should note that this was open label, the event rates were driven by repeat revascularization, and if you know that your patient has an FFR of 0.8 or less, you're going to say, "Okay, if you have chest pain, come in and we'll do a revascularization." I think there are lots of little issues [with the study], but the gist is that ischemia-driven revascularization is a good thing.
Dr Fuster: Jag, I have a question for you. As I mentioned at the beginning, about 50% of these patients don't have stress testing. On the one hand, this is bad because that's where you can see ischemia. On the other hand, stress testing doesn't localize the artery with the problem. Now from your perspective, how do you see these problems that we face today? Patients are going to the cath lab without us really having enough information ahead of time and then once they are there we get all the information and decide [to intervene].
Dr Singh: It's almost a rhetorical question. I personally think that everybody should get a stress test to see if there's any functional level of reduced blood flow. Then based on that test, decide whether they need any intervention or angiography to delineate if they have stenosis, and then do an FFR to find out if there is a stenosis that needs further intervention. I would actually pull back [further], evaluate their symptoms, make sure they have a stress test, and based on the stress test then decide if they need further workup.
Dr Fuster: Michelle, what's your reaction? I want to emphasize what Roxana said, this is an important study. We learn a lot about physiology and understanding, but how do you react to all of this? How will you handle your patient with a stable disease tomorrow? This is really what we are talking about.
Dr O'Donoghue: It is such an important study, and we'll also have the results of the ISCHEMIA trial coming down the road to think more about stress testing and whether that can help risk-stratify our patients as well and help guide decision making. Roxana's point about it being an open-label trial is an important one because when it comes to an end point like urgent revascularization, there is concern about bias even if it's not intentional, so it does give me a little bit of pause.
It is reassuring that the landmark analysis shows that over time there does appear to be a strong directional trend for a lower incidence of death or MI. But I think we can't discount the fact that the landmark analysis means that you're starting a little bit later, and there was a strong signal toward a hazard early on. We need to consider the entire follow-up from the time of the PCI right through to the two-year mark and consider the fact that patients who get PCI will be at that early risk of coronary events right after their procedure.
Dr Fuster: Neil, I'm interested in your view as a surgeon. We are all talking about PCI, but I thought that in multivessel disease when you have a SYNTAX score that is a little bit high, you should use revascularization with bypass. Are we missing something here?
Dr Moat: I would agree the SYNTAX trial is pretty clear that the outcomes are better in chronic stable angina with triple-vessel disease with surgical revascularization vs PCI. But what I like about this study is it's adding to the evidence that we should be assessing functional ischemia and treating that rather than treating two-dimensional anatomy. I think that message pertains to surgeons as well as interventional cardiologists. My take-away is that we have to move more toward stress testing before we do invasive imaging, and then look at each artery to see if there's significant stenosis that affects function. If there isn't, we shouldn't be doing PCI on it, and if there isn't we shouldn't be grafting it when we operate. I think that's one of the key messages.
Dr Fuster: Roxana, I'm going to present a patient to you. I'd like to hear how you would handle this. He is a 55-year-old man with a sedentary job, he has occasional angina and comes to see you. You do a stress test, and you are worried about it. A young guy, some problem with ST depression on echocardiography and so forth. Then you do an angiogram, because we are worried, and you find three-vessel coronary artery disease. Do you start pushing catheters inside to assess the gradient? Are you going to do the SYNTAX score? Are you going to do both? How would you manage him?
Dr Mehran: As you know, in our lab at Mount Sinai, (and in many other labs) the SYNTAX score has become part and parcel of what we do. When there is three-vessel disease, depending on the risk factors and the anatomy, we'll take a step back, especially if the SYNTAX score is high. If there is diabetes involved, it's a whole different story, as you know based on the FREEDOM study.[9] But if the decision is made to proceed with PCI after a heart team has met, there's no question we use FFR. It's similar to what electrophysiologists do, they map to see where the issue is and ablate the VT or the AF by mapping with the techniques they have. Even though we have a stress test that gives us the functional characteristics as a whole, atherosclerosis is a ubiquitous process, as we just talked about, there are lesions everywhere, and maybe only one or two of them need to be treated, so the use of FFR- guided PCI has increased.
Dr Fuster: In the past five years the SYNTAX score anatomical assessment and an assessment of the physiology has really been very helpful to us. John, you probably are thinking these guys are crazy, why don't they prevent the disease?
Dr Chapman: Certainly, but it seems to me, Valentin, that this discussion focuses on a critical area where we still haven't arrived technologically and that is noninvasive hybrid imaging. It seems to me that if we could have more information on that stenotic lesion and on those related vessels in the multivessel-disease patient, that could be tremendously helpful, because we could of course have a stenotic lesion that is relatively stable.
ODYSSEY: The PCSK9 Inhibitor Alirocumab in FH and High CV Risk
Dr Fuster: Well this is coming. In the next 10 years, I think we are going to see a lot of change. I predict that MRI will play a very important role in the anatomy as well as in the physiology assessment for localizing the lesions. It's going to be quite exciting.
We've discussed cardiac failure, CVLPRIT, lots of questions about how to manage the nonculprit lesion in acute MI. Now let's discuss something that is at the heart of the physiology in patients with a stable disease. There were a couple of interesting presentations about the new lipid-lowering agents that are coming. I think it was in the early 1990s when the 4S study[10] came out, and it was extraordinary. It was a breakthrough in terms of the reduction in events by lowering cholesterol. Well, I think we are getting into that now with the new approach.
Let's discuss the ODYSSEY Long-Term Study,[11] which was presented by Dr Jennifer Robinson;there are a number of studies on the so-called [proprotein convertase subtilisin-kexin type 9] PCSK9 inhibitors. PCSK9 is a molecule that blocks the entry of cholesterol into the cholesterol receptor. If you inhibit it then cholesterol gets out of the blood—basically we are talking about inhibiting an inhibitor. The drug in the ODYSSEY studies is called alirocumab.
These studies looked at patients with heterozygous familial hypercholesterolemia and then people who were at high risk of coronary artery disease, and the number of patients were close to 2000, so we are dealing with a good number. The long-term study evolved because of patients who either didn't tolerate the statins or despite being on a high dose, they still had hypercholesterolemia. I think it's important to note that they used a relatively high dose of alirocumab: 150 mg subcutaneously every two weeks. This is a relatively high dose compared with the other studies that we will also mention today that did not show a reduction in hard events.
At 24 weeks, there was a significant decrease in LDL concentration, at least by 60%. Now we have a post hoc analysis (not perfect), which revealed that in patients who used the drug, alirocumab achieved a 54% reduction in the relative risk of cardiovascular events (coronary death, non-fatal MI, fatal ischemic stroke, and unstable angina). It's post hoc, but it's the first time we've seen a reduction in hard end points with PCSK9 inhibitors. John, you are in charge. This is your field.
Dr Chapman: Well, Valentin, we do indeed live in exciting times in the field of lipid management. What is absolutely fascinating in the data that you've described is that the separation of the curves for events was at a very early stage—almost within a month. This actually is quite coherent with the data from some of the critical statin trials. If we think back to PROVE-IT [12] with the high and the low dose of atorvastatin, we saw separation of the curves in a very high-risk secondary-prevention population after about two months (between two and three months). It's totally logical that with a greater degree and an earlier reduction in LDL-C (in the order of 60%) primarily in FH patients, we're seeing an earlier clinical benefit. So that is absolutely tremendous.
I think the other point here is that from very recent population studies, with new DNA-sequencing technologies of course, we've realized that the frequency of familial hypercholesterolemia is twice as high as we ever imagined. We're actually in a ballpark now approaching 40 million individuals worldwide who are carrying at least one defective gene for the LDL receptor.
Dr Fuster: It will be good adherence because you give this subcutaneously.
Dr Chapman: Absolutely, and of course as we get more and more experienced with the statins, we're seeing that this so-called statin-intolerance phenomenon does indeed have a pathophysiological basis and certainly from Paul Thompson's STOMP trial,[13] it really does seem that we're focusing in on a phenomenon of attenuated energy production in skeletal muscle, in up to perhaps 10% of statin-treated patients. Quite frequently, we're in a very unexpected situation, where an individual can be on a statin for even a number of years. For example, with intense exercise, all of a sudden the CKs will skyrocket.
Dr Fuster: So nice to see you so excited. Let me ask you Michelle, are you as excited as he is?
Dr O'Donoghue: I think everyone is excited about the PCSK9 inhibitors. We're now seeing about a 50% to 60% reduction in LDL-C across the board, even in the heterozygote FH patients, so it really does seem to be quite consistent in terms of that pharmacodynamic effect. Now we have data on critical events that are also very encouraging, and I was struck by the extremely early separation of the curves that PROVE-IT supports the concept, but of course that was in an ACS population.
Dr Fuster: The side effects are small.
Dr Chapman: The adverse effects have been in a similar frequency to the placebo groups. There may be a small elevation in those with nasopharyngitis, clearly some injection-site reactions, and perhaps a small increase in upper-respiratory-tract infections. The tolerability and the safety at this point in time (with the limited number of patients that we have across alirocumab, evolocumab, and to a lesser degree bococizumab) gives us a great deal of optimism that these will be very well tolerated over significant periods of times.
Dr Fuster: I should briefly mention that there were two other studies presented, one by Michel Fournier, the ODYSSEY FH I and FH II.[14] The reductions in LDL-C are the same. These were patients with familial heterozygous hypercholesterolemia who had about a 50% reduction in the level of LDL-C. Then the ODYSSEY COMBO II[15] study presented by Chris Cannon in patients at high CV risk where the dose used is lower, it's 75 mg twice a day, so I think the issue of the dose may become important.
In terms of giving that subcutaneously every two weeks, I'd like to hear, Roxana, your reaction.
Dr Mehran: I'm also extremely excited because not only are you seeing a reduction in LDL but for the first time we're seeing an HDL elevation in these patients, which is tremendous.
Dr Fuster: A drop in LP(a) that is very significant.
Dr Mehran: These FH patients are patients that we don't know what to do with because we don't have good therapy. But once again, we still need long-term outcome studies before we get so excited; I'm very excited about the separation of the curves. We've all been excited before; it needs to be replicated in the very large outcome study, which I'm sure is being planned.
Dr Fuster: Neil.
Dr Moat: I agree with Roxana, I think it is very exciting to see such a dramatic effect, but it's very early days.
Dr Fuster: Are the surgeons going to be put out of business?
Dr Moat: I think we can find other things to do.
Dr Singh: I'm excited seeing everybody's excitement. I look forward to assessing its antiarrhythmic properties.
Dr Fuster: This is fascinating, and I think it opens a tremendous field of hope. All of us deal with patients with familial hypercholesterolemia. I see a number of young patients, even children aged five years with cholesterol levels of 500 mg/dL, and what do you do? You do almost like dialysis, but the fact of the matter is that these agents could be a tremendous hope for these families. John, what is the percentage of people in the population who have heterozygous familial hypercholesterolemia? Or give us a sense of the reality.
Dr Chapman: The estimates from the Netherlands and from Denmark at this time and a little bit from Iceland and UK were around about one in 230 individuals, so about 0.4%, 0.3% of the general population.
Dr Fuster: And then you have the high-risk population and the patients who can't tolerate statins, etc, etc.
Dr Chapman: The other point if I might, Valentin, is that in one or two of the coronary cohorts where DNA analyses are being performed, we're seeing an enrichment of FH patients, as you would predict in these CHD cohorts, so clearly there's a red light out there in cardiology for improved detection and diagnosis of these patients and of course aggressive treatment as early as possible, because of course from the Mendelian-randomization studies we know now the earlier we treat, the better.
FOCUS: Polypill vs Three Single Drugs
Dr Fuster: We are going to discuss the last study, which actually touches on adherence, which is one of the problems that we face today. I will be presenting the [ FOCUS ] polypill study[16] later today, so this is my rehearsal. This is basically the first study done on adherence to a polypill following myocardial infarction. It took six years to design this study; developing a polypill is very complex and very expensive.
We did this study in five countries: Italy, Spain, Argentina, Brazil, and Paraguay. The study assessed two different aspects of adherence. There were 2000 patients following myocardial infarction. We asked three questions: One, are the physicians prescribing the drugs that should be prescribed? The answer was yes, 95% right. That's an interesting finding for different countries with different socioeconomic issues. The second question is, Are the patients taking the drugs? And the reality (which is dramatic) is that less than 50% are taking the drugs after six months.
But the most interesting part is [the third question]: Why? Why don't people take the drugs and I'm sure this applies to other entities? The following factors were associated with nonadherence: the younger you are, the less you comply with the medication, which is interesting; the more complex the medication regimen, the less you comply. And the other factor is depression; it has a significant impact. I wouldn't say the world is completely depressed, but there are lots of concerns in people's lives, and this is a factor in taking the drugs. By the way, this was statistically significant in all five countries.
Having family support makes a tremendous difference. And of course, whether the drugs are provided by your insurance and so forth. Dr Stuart Pocock was involved with the statistics. Roxana, you were party to this. We gave one group the polypill, and the others got the pills separately. The pills we are talking about are aspirin, ramipril, and simvastatin.
To develop this polypill, we went over at least 90 polypills because pharmacologically you have to ensure they act exactly the same when you put the pills together vs separately. It's very difficult and complicated and very expensive. The laboratories of Grupo Ferrer in Barcelona took on the task.
We randomized 700 people to the polypill vs the three pills separately, and the adherence was significantly better in the people who took the polypill. Actually the adherence was better than we had expected: 65% vs 55%, a 20% increase in the adherence. Once a patient is in a trial, they are more compliant. This applies to all trials. The results were very significant, and we are now planning a study of 2000 people across the world where we are going to use the polypill and measure events, not just adherence.
I feel as excited as you feel with the PCSK9 inhibitors because we are beginning to pay attention to this tremendous lack of adherence, which explains a lot of the recurrent events, so what do you think?
Dr O'Donoghue: Well, I think you hit on the important point, which is that the polypill really puts the spotlight on the question of adherence. We've had so much discussion recently about personalized medicine and trying to tailor therapies specifically for the individual patient with hot topics like clopidogrel response variability. But when you look at the number-one reason for response variability, it's noncompliance. It's a thrilling direction to think about in terms of going back to the beginning, how do we work on compliance, adherence, making sure that the drug prescribed is taken by the patient before we shift gears and think too much about tailoring therapy.
Dr Fuster: I am quite skeptical about personalized medicine in cardiology because how can we do personalized medicine if 50% of the people are not taking the drugs they are supposed to take?
Dr Singh: I agree, I think we have a social obligation to ensure that the medications that we prescribe to patients are taken, because in this current era of healthcare reform and limited resources, we'll end up spending more money taking care of complications that the patients have because they did not adhere to medications. Finding innovative strategies to address that whether it's through the polypill or through insurance strategies. There are some interesting trials going on like Synch Med , where they actually synchronize when you refill all your prescriptions for different diseases, so that you get them all at one time. I think the polypill is a great idea. I think along with that there may be other strategies that may facilitate it, and I think it's going to have a huge impact.
Dr Fuster: Well this leads to the next question, Roxana, isn't why people don't take the pills the more important question? We have to get to the root of the problem.
Dr Mehran: You picked up on depression, and in the PARIS registry, we picked up on education and whether or not the patients received teaching about their medications; those are really significant issues, because even with the polypill, although you had a significant increase in adherence, there were still almost 50% of the people who did not take the medication. That's the next big step. This is a huge area and a very important of health concern, and hopefully the government will turn their eyes toward something like this. Because if we really want to make an impact on improving the health outcomes of our patients, we've got to dive into these simple questions, rather than the complex innovative approaches.
Dr Fuster: Neil.
Dr Moat: I agree, and I think in so many fields we spend a lot of time on patient education (this is not my field), but I don't get the impression that much time is spent in informing the patient of the importance of taking the tablets regularly. I'm kind of an end user in this system, but patients who come to see me have usually seen several general physicians, cardiologists, etc, and most of them are not taking all their tablets.
Dr Fuster: It's interesting what you were saying about simplicity. John, we have an epidemic. It's the number-one cause of mortality, and frankly we have to go to the root of the problem. There's a lot of behavioral risk factors, and one of the fields I'm working on is with children age three through six because I learned from Sesame Street that that's the age we develop our behavior. Shouldn't we pay more attention to the roots of the problems rather than all these new technologies and drugs and so forth?
Dr Chapman: Well, Valentin, there are two points that immediately come to mind. We talk about patient education but we don't talk about patient needs. We are not available to respond to patient needs. A brief example, in the instance of a patient with a severe form of familial hypercholesterolemia, there are marked aesthetic consequences, xanthoma, xanthelasma, [and] patients are quite conscious of those manifestations. They can impact a patient's life. The difficulty that we all face is that there's such tremendous pressure on the time that we can spend with a patient. I think it's 17 minutes at the moment in France and falling, so we clearly need to think of a second tier of support.
Dr Fuster: Absolutely.
Dr Chapman: The other point is if only we could get pinpricks from children at vaccination because if we have 40 million FH patients around the world; we've got the therapeutic approaches to help, but can we detect them? It's a tremendous public-health question for us all, and I do feel very optimistic, Valentin, that the polypill approach in many areas of the world could help us tremendously.
Dr Fuster: Well I don't know if we have gone from celebration to "something is not working," but this show worked, and I'm really happy in terms of the discussion. I think we touched on a number of issues that are important today in our field of cardiovascular diseases, and I would like to thank the five of you for being here, and I hope you the audience learned something. Again, this is the European Society of Cardiology 2014 Congress in Barcelona. Thank you.
News stories on some of the trials discussed
PARADIGM-HF: New Drug Class Outclasses ACE-I in Chronic HF
Dramatic Drop in MACE With Complete vs Culprit P-PCI
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Cite this: The Cardiology Show From ESC 2014 with Dr Valentin Fuster - Medscape - Sep 03, 2014.
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