Editor's Note:Dr Fuster packs in all the late-breaking trials from the American Heart Association (AHA) 2014 Scientific Sessions in this bumper edition of the Cardiology Show. Our chair and panelists Drs Januzzi, Mauri, O'Donoghue, Watson, and Yancy discuss the top studies on the duration of dual antiplatelet therapy after stenting, biodegradable-polymer stents, and ezetimibe plus simvastatin. Negative trials on CT angiography in patients with diabetes, aspirin in primary prevention, losartan vs atenolol in patients with Marfan syndrome, and CABG surgery with or without mitral-valve repair in patients with ischemic mitral regurgitation (MR) are also addressed. To conclude, Dr Fuster summarizes five curious findings that give pause for thought.
Dr Valentin Fuster: I am Valentin Fuster from New York. We are at the Chicago Scientific Sessions of the American Heart Association, and I'm very pleased to have with me five distinguished colleagues. We are going to be discussing what has been an outstanding meeting from the point of view of clinical trials and presentations.
On my left is Dr Karol Watson, professor of medicine, Department of Cardiology at the David Geffen School of Medicine for the University of California, Los Angeles [UCLA] and UCLA program in preventive cardiology. Next, Dr James Januzzi, who carries the name of two good friends from the Massachusetts General Hospital. He is the Hutter Family Professor of Medicine, Harvard Medical School, Boston, and Roman DeSanctis endowed clinical scholar, Massachusetts General Hospital. Roman, if you are watching, we want to say hello to you. Then we have Dr Michelle O'Donoghue, associate physician, cardiovascular division, Brigham and Women's Hospital and assistant professor of medicine at Harvard Medical School. And at the end on my right is Dr Clyde Yancy, well-known to all of you. He has been in this program many times. Thank you. He is the Magerstadt Professor of Medicine at Northwestern University Feinberg School of Medicine and chief of the division of cardiology at Northwestern Memorial Hospital in Chicago [IL]. And finally, on my right is Dr Laura Mauri, associate professor of medicine at Harvard Medical School, interventional cardiology, and director of clinical biometrics at Brigham and Women's Hospital in Boston.
Well, we have a lot to cover today. I would like to first, beginning with two or three important trials, and then we'll go into a fourth trial, which was negative but important because it may change our practice. Then we will discuss some curiosities that we learned in this meeting.
Laura is very well known to all of you—she has been photographed everywhere and is on television. She did a fantastic job on the DAPT trial[1,2] that we are going to be discussing. It is one of the best-executed trials that I have seen for a long time, and it compared 12 or 30 months of dual antiplatelet therapy after drug-eluting stents. This trial evolved from the [Food and Drug Administration] FDA back in 2005 to 2006, when there was concern about stent thrombosis, and they were not happy for us to stop antiplatelet drugs at one year and wanted to know how long you should prescribe them for.
Let me briefly describe the study. The patients were enrolled after they had undergone coronary stenting in which a stent was placed, and after 12 months of treatment completed either with clopidogrel or prasugrel plus aspirin, patients were randomly assigned to continue receiving both drugs or to receive just aspirin for about 18 more months. The study actually looked at a number of issues. There are six different pieces of data. Each of them is quite interesting.
The first one is stent thrombosis—it was extremely low. It was 1.4% in the group that was treated with aspirin alone and 0.4% and in the group that was treated with aspirin and prasugrel or clopidogrel for a longer period of time. Just 0.4%, so a very low rate, which is notable because the FDA was very concerned about this issue. The second item (and one of the main end points) was adverse cardiovascular events—a composite of death, myocardial infarction, or a stroke. Here we have the difference again in favor of longer duration of the two medications. It was 4.3% in the group with dual therapy and 5.9% in the group that was followed with aspirin alone. Now what is quite interesting is that when you look at the components of the composite end point, most of the difference was in the rate of myocardial infarction. What can we tell from this finding of very low rates of stent thrombosis and relatively higher rates of myocardial infarction? A large number of the events had nothing to do with the stent, which was the original driving force for the FDA to ask for this trial. Most of the events were related to the native disease, and I think this is fascinating for all of us who treat these patients.
There were some negative aspects of longer-duration of DAPT. The mortality rate was a little higher in the dual treatment arm—2% vs 1.5%. This was not related to cardiovascular events, and maybe it is something that happened by chance. The bleeding, however, was significantly higher in the group treated with the two antiplatelet medications—it was 2.5% vs 1.6%. Perhaps the most striking and convincing feature of this study was when the drugs were discontinued—that is, when the dual therapy was discontinued—the number of cardiovascular events over a period of 90 days increased. This tells us that obviously the drugs are doing something. To me, this is the clearest proof that the data are quite real. This is what the study showed. Now I'd like to ask you. . . . The first that I would like to ask you, Laura, is the following. If I recall in the CHARISMA trial, in the CURE trial, they found exactly the same. When two drugs—in that case aspirin and clopidogrel— were stopped, the difference in MI was significant, and this was related to the native circulation and had nothing to do with the stents. Do you recall the same thing?
Dr Laura Mauri: Yes, I think that's right. There were indications in subgroups of other trials like CHARISMA and CURE. In CHARISMA in particular, the symptomatic patients, which perhaps those were the markers for more serious atherosclerosis, had a benefit to treatment. It is a preview of what we saw in the DAPT study.
Dr Fuster: Do you think we should be much less obsessed about the stents vs the native circulation based on your study?
Dr Mauri: They are two separate things. The most interesting finding of DAPT is the non–stent-related myocardial infarction, and it represented more than half of the cardiac events that happened in the trial. The take-home from that is that the antiplatelet therapy had an impact on secondary prevention and, as you said, the rate of events related to the stents was really low. So as you go further and further out, they are quite safe. I don't think we should think that we can never stop therapy, because it probably is okay to stop for short periods of time. But these medications seem to help prevent events.
Dr Fuster: Depending on how we manage our patients. Let me ask you the final question, then we'll go to my colleagues. If you had combined the ischemic events (omitting stent thrombosis) with the bleeding, the trial results would not have been significant. Is that not correct? Because the two other trials that we'll discuss in a moment stopped DAPT at 6 months, and the end point in those trials is a combination of ischemic events with bleeding. I just want to be sure that at least we address that.
Dr Mauri: That's a really good question, because it often comes up in clinical trials. It especially comes up in smaller clinical trials because you can't power a small study to look at a rare end point. This study was powered for stent thrombosis and for clinical events because you want to look at both of those things. Smaller studies can't do that. The problem with combining events that are so different from each other is that they go in opposite directions with the treatment, so it's hard to make any kind of claim about noninferiority.
Dr Fuster: Thank you. Obviously she was the principal investigator of the trial; this is why she became so famous. But in the last two days, she's been very busy, and you tell me you had a good night of sleep and a good meal.
Dr Mauri: That's right. For the first time in a while.
Dr Fuster: You deserve it. What do you think, Clyde? What do you make of this study?
Dr Clyde Yancy: The first thing we need to do is congratulate Laura. This has really been an incredible task and a long journey, and it's been ably and capably led by Dr Mauri, so congratulations for that.
Dr Mauri: Thanks, Clyde.
Dr Yancy: I think that we have a database now that does change practice. Not only does it change practice, but we really have to think about whether this should change our guidelines. Is this not of sufficient importance that those of us who convene groups and populate clinical-practice guidelines should look at this information and ask if we need to make some additional statements about antiplatelet therapy after interventions? I think it's at least worth the conversation. This was a perfectly executed trial for an important problem.
Dr Fuster: Okay, Michelle?
Dr Michelle O'Donoghue: Everyone has really been eagerly awaiting these results for a long time, so again, congratulations. It's so great to actually have this database. I was really quite struck by the dramatic reduction that we saw in stent thrombosis as well as in major adverse cardiovascular events. You noted that the stent-thrombosis rates were low, but nonetheless, this was after 12 months and this is not a purely ACS population. These were patients who'd undergone elective stenting as well. I was actually quite surprised by the degree of reduction that we observed in cardiovascular events, and the bleeding signal, I have to say, was not as great as I might have thought for a placebo-controlled period of time.
Dr Fuster: Thank you. James?
Dr James Januzzi: I think that's a really important point and very helpful for clinicians and patients alike in that (as Michelle said) the bleeding risk was not the sort of catastrophic and fatal bleeds that we sometimes worry about. This is a very nuanced area. Regardless of the guidance that it would be permissible to stop clopidogrel at a year, clinicians frequently continue therapy because there's a lot of uncertainty and patients ask frequently, "Is it okay for me to stop my clopidogrel or prasugrel?" These data really indicate that it is relatively safe to continue, and it was associated with a substantial impact on longer-term clinical outcomes beyond just that of the stent.
Dr Fuster: Yes. Karol?
Dr Karol Watson: Again, congratulations on the beautiful trial. I was very struck by the non–stent-related events, and that really goes back to what we've always known. Antiplatelet therapy in secondary prevention is important, and when there's atherosclerosis in one vessel, it's in the entire coronary, cerebral—probably every vascular bed—and plaques are rupturing all the time, so making sure that there's an antiplatelet agent on board makes sense.
Dr Fuster: Laura, the last few days I have been quoted as saying that this will not change my practice, and I think this has been misinterpreted. I have been very influenced by the CHARISMA trial and the CURE trial. This has been my practice. See what you think. In patients with a stent who are at high risk, I continue the two medications forever. It was based on what we learned from these trials which were in stable coronary disease—native disease. On the other hand, in patients at a very low risk, I was following the data from the European trials (we have more today). For example, in a patient who has only one or two stents with perhaps some predisposition for bleeding, in those patients I was stopping dual antiplatelet therapy at 1 year, and now I am beginning to stop it at 6 months. This is why the DAPT trial doesn't change what I do. Do you think this is a reasonable approach?
Dr Mauri: I think it's a very reasonable strategy before the trial. I think we know a little bit more, though, that might change your practice when thinking about the patients who benefited beyond 12 months. It wasn't just the high-risk patients. Just about every subgroup of patients had benefit. And there was a wide range included. Half the patients had risk factors for recurrent ischemic events, and half the patients didn't, and they both had equal relative benefit with continued therapy to prevent stent thrombosis and MI. That shook up the way that I thought about this, because now when I see that relatively healthier patient back at 12 months who doesn't have extensive risk factors but is doing well on the medication, I'll probably continue them on it. I don't think I would have done that before.
Dr Fuster: James, what would be your practice? Today a patient comes in with a stent and the patient has a proximal lesion with the stent, what do you do afterward.
Dr Januzzi: As the discussant at the session said, in the end it comes down to individualizing what we do for our patients. I look at the angiogram of the patient, I make a decision based on the coronary anatomy—if they've got a high-risk appearance for stent thrombosis as well as subsequent events from non–target-lesion plaque rupture. Generally, I continue dual antiplatelet therapy. My practice has been largely to continue the drugs in the absence of a compelling reason to stop. I am reluctant to suspend dual antiplatelet therapy if I have patients with moderate to smaller stents, overlapped stents, multiple drug-eluting stents, bifurcation stents. Unfortunately, in our more modern practice, that's what we see more and more—patients with more diffuse disease.
Taxus Liberté, ITALIC, and ISAR SAFE
Dr Fuster: I'd like to ask you a question about another trial that was presented using the Taxus Liberté drug-eluting stent and using prasugrel. The data were practically the same, but what was striking to me was the higher number of events in the control group (vs the DAPT trial). Is this perhaps because that particular stent is less reliable than the others?
Dr Mauri: First of all, the reason these data were presented separately from the main DAPT trial was because the data safety monitoring board [DSMB] saw an uptick in events as patients came off the drugs in the subgroup implanted with that stent. We know from head-to-head comparisons that there's a higher rate of stent thrombosis with the [paclitaxel-eluting] Taxus stent compared with an everolimus stent. The important thing is that in the overall study we still saw a consistent reduction with dual antiplatelet therapy even for the paclitaxel stent.
Dr Fuster: Michelle, let's see if you solved the issue. There were two more trials presented during this session. There was another where most of the patients were from France, I believe. It compared 6 months vs the 24 months of DAPT and included about 2000 patients and they used aspirin and clopidogrel. After 24 months, the number of events was very low in terms of the revascularization, stroke, and myocardial infarction. It was 1.6% vs 1.5%. There was no difference. The stent thrombosis rates were 0.3% vs zero.
Then the other study, comparing 6 months vs 12 months, was largely based in Germany with 4000 patients. They are actually very similar in that they pooled together the bleeding with the events, but the number of events was so low. What is happening here? Is it that the stents used in the European trial are third-generation or rather second-generation drug-eluting stents? This is a puzzle to me. How can you explain that in all these European trials, they can stop at 3 or 6 months and then you have the fantastically run DAPT trial and you see something different?
Dr O'Donoghue: I think the answers are really in the numbers. Because, leading up to the presentation of the DAPT study, there were a fair number of studies that had suggested that perhaps we could get away with a shorter duration period of DAPT. But when we look at the width of those confidence intervals, they're really quite wide. I think that one of the novel things about the design that we have for DAPT and one of the issues you already touched upon is that we had that unique period of time where we were actually able to follow patients at the end of the study after discontinuation of therapy. One of the things that really struck me was just how quickly the rate of cardiovascular events appeared to increase after discontinuation of dual antiplatelet therapy.
Dr Fuster: James, do you think this is a statistical power issue?
Dr Januzzi: Absolutely. The only trial that was presented in that session that had the kind of power necessary to address the question was Laura's study.
Dr Fuster: This is fantastic. I don't know how this is going to change practice. I'm focused on the native disease as I have always been because this is what I have studied all my life.
Dr Mauri: One thing is that you probably were prescient in treating people this way, but across the world there's been so much variation in practice. Even in the United States for a time when we did the trial, we had many physicians who didn't want their patients to be randomized because they thought they should continue on DAPT forever. As time went on, you saw the opposite, where the trend has been to shorter therapy. I think that's why we need trials, right?
Dr Januzzi: Absolutely.
Dr Fuster: Yes. I think it's a good moment to perhaps describe two trials that were related to stents to see what your opinion is. We are now talking about the so-called biolimus-A9-eluting stent which is a third-generation stent with a biodegradable stent polymer. This is a type of stent that was used in a European study[8,9] presented in this meeting (the presenters were from Switzerland).
When you review the literature on biodegradable stents, there are two issues, at least as I understood it. One is that these newer stents may cause problems when first implanted, but it has been proven that this is not the case and that they are noninferior in that aspect. This was shown in the EVOLVE II study, which was also presented in this meeting and showed no difference for the Synergy stent compared with the everolimus second-generation stents at 1 year. The question is what happens after 1 year? It was my understanding that after 1 year, the material is gone, so there should be no thrombosis.
And now here comes a study that really shakes up our knowledge. I won't go into details, but as I said it was a European study with more than 2000 patients in which they were randomized to three types of stents. The biolimus-A9-eluting stent, the second-generation everolimus stent, and a bare-metal stent. To make a long story short, there was no difference in terms of the events at one year. But when they go into 2 years, there was also no difference in stent thrombosis and MI. I thought there was supposed to be with these biodegradable stents. What is wrong? Maybe I misunderstood. What do you think, James? What is happening here?
Dr Januzzi: The earlier hope with biodegradable stents is that the possibility of fixing the vessel—dealing with the target lesion mechanically until the neointimal proliferation has finished and then the scaffolding dissolves—would reduce the longer-term consequences of the presence of a device in the coronary arteries. The early data with polymer stents—either polymer coated or just dissolvable biodegradable stents—is that they actually triggered a biological reaction to the scaffold, to the device itself, which accelerated restenosis. With these devices, the early data suggested that there wasn't such a reaction, and so the hope would be that we would see better long-term outcomes, but that's not what they saw.
Dr Fuster: Karol, what is your opinion?
Dr Watson: We have seen [intravascular ultrasound] IVUS studies that show that the biodegradable scaffolding is still there at 6 months and a year, so we're not getting complete biodegradation like they thought.
Dr Mauri: Can I step in to clarify these two studies. There are completely biodegradable stents that are being studied, but that is not what was studied in these trials. The one that is furthest along in development is the Absorb stent, which elutes everolimus and is fully biodegradable, but it takes 3 years for it to be fully absorbed. There still may be a benefit to that because you can therefore access the artery more easily. BASKET PROVE II and EVOLVE II involved durable stents with a biodegradable polymer. They're not the same. In this case, you still have the stent platform remaining, and that has advantages because you can get a better acute result compared with some of the bioabsorbable stents that are thicker stents than the bioabsorbable polymer stents on durable scaffolds.
I think the two studies were really fascinating because they promise that perhaps we can have less polymer over time. They're simply noninferiority studies compared with the existing stents. To get the data to whether they're actually safer, we're going to have to wait.
Dr Fuster: We're summarizing by saying that the DAPT trial shows the stent is important in your life, but maybe the native circulation is as important or more important. That's number one, and number two is these biodegradable polymer stents or absorbable stents need more time because until now we don't have strong data in favor or not. Is this fair?
Dr Mauri: Yes. I think one of these stents probably will have enough data to be able to support its use in the US in the near term because it's as good as the stents that we use right now. To show what the advantage is will take time.
Dr Yancy: There's another point here, because as you identified, the event rates with contemporary PCI are so low now that trying to find a superior platform may be a very difficult thing to do.
Dr Januzzi: It may be more about safety than about efficacy.
Dr Yancy: Exactly.
Dr Fuster: Let's move into a different field now. We are going to discuss one of the most interesting studies presented here also. The so-called IMPROVE-IT trial—the famous study that we have been waiting for 9 years. Ezetimibe went through a bad period of time, but remember one thing. In some of the early studies they used the "surrogate end point" of intima media thickening [IMT]. I just want to say once and for all that IMT is not atherosclerotic disease. It's just a reaction of the media with time. There were a number of studies on other drugs that used IMT as an end point. I would never use IMT to make a decision about any drug. Having said that, I think what I am most impressed about this trial is how patient investigators have been working with this particular approach when the cholesterol levels were close to normal.
I believe the chairs of the trial were Drs Braunwald and Califf, but the trial was presented by Dr Cannon. I'd like to go into some of the details, because this is an important study. It certainly could change practice. We are all in agreement that no lipid-modifying therapy added to statins has thus far shown anything significant. I'm talking about fibrates, niacin, cholesterol-ester-transfer-protein (CETP) inhibitors, and so forth. Recently the guidelines emphasize that we should use a statin or nothing.
Dr Watson: Not nothing.
Dr Fuster: I knew you wouldn't let me away with that. But drugs that were not statins were put in question.
Dr Watson: We recommended the maximal intensity of statin that could be tolerated, and if the clinician didn't see any adequate LDL reduction or the patient wasn't able to tolerate it, addition of a nonstatin with evidence would be okay.
Dr Fuster: Ezetimibe was very attractive at the beginning. If the cholesterol theory holds true, then the decrease in blood cholesterol levels by this drug, which affects the absorption in the GI tract, could be quite meaningful. The investigators had three questions. Does lowering the LDL cholesterol with a nonstatin agent, ezetimibe, reduce cardiac events? Is lower better? And the third relates to safety.
The types of patient entered into this particular study (close to 20 000) were hospitalized for an acute coronary syndrome. I think this is a very important point. We're not talking about primary intervention here. The patients had high-risk features. I won't list them all, but they had bypass surgery, prior vascular events, diabetes, etc. What was striking to me was that the LDL cholesterol had to be about 50 to 125 mg/dL, so these patients were very well treated. How are you going to have an impact when you are already beginning with a low-normal cholesterol level? I was impressed that the investigators pursued this study. These patients were treated on ezetimibe 10 mg and simvastatin 40 mg or simvastatin alone and followed for a minimum of two and a half years, and I believe it was an average of 6 years. In terms of the LDL-cholesterol levels with the combination therapy it dropped from about 70 mg/dL (69.5 mg/dL) to 53.2 mg/dL. This was known already before. Here comes the primary end point, which was cardiovascular death, myocardial infarction, and unstable angina requiring hospitalization, coronary revascularization, or a stroke. The incidence of these events was decreased from 34% to 32%—not impressive with 20 000 people, but certainly this was statistically significant. Then they looked at the most critical events death, nonfatal MI, nonfatal stroke, and there was a decrease in the incidence of events from 22.2% to 20.4%. Then they looked at the individual aspects–MI, stroke—and also there was a trend, always in favor of the combination of both drugs.
In answering the three questions, they write in their conclusions that lowering LDL-C with ezetimibe reduces cardiovascular events, that even lower is better, which is true. They also confirmed the safety of the drug which I won't go into to. James, how you react to this? Is this going to change your mind?
Dr Januzzi: No. It confirms that the cholesterol hypothesis still lives and that achieving lower values for LDL-C, whether driven down by statins (the dominant therapy we should be giving our patients) or supplemented with ezetimibe, results in lower values and subsequently lower cardiovascular events. We've been aiming for low targets all along. The question now is, do we go back to target values? The guidelines have changed somewhat, being very statin-centric, appropriately, talking about getting patients on potent statins at maximal doses. Do we now take a step back and look for a target? If a patient on 80 mg of atorvastatin has an LDL-C of 70 mg/dL, should we be shooting for 53 mg/dL? As the investigators showed very nicely, if you plot achieved LDL cholesterol vs event rates, IMPROVE-IT falls right on that slope, suggesting that lower target values for LDL cholesterol may very well be associated with better outcomes.
It changes my practice only inasmuch as it confirms my belief that lower values are the most desirable outcome that we can shoot for.
Dr Fuster: In the clinical trials of statins when they look at side effects, they look at pain, rises in [creatine phosphokinase] CPK levels, and so forth. But those of us who practice medicine know there are lots of side effects, including poor sleep, headaches, fatigue, sexual dysfunction. There are a lot of things that happen when patients take statins. I would say 15% to 20% of people experience side effects. Based on this, would you give the highest dose of statins to patients for secondary prevention? Because I believe that you need to add another drug in a large number of patients rather than using the highest-dose statin.
Dr Watson: I completely agree with what you say. I'd like to react to what you said at first. Lower is better with proven therapy. Statins have been proven, and now we have proof of ezetimibe. Lower was not better with CETP inhibitors or fibrates or niacin. I would strongly recommend that all data be based on outcomes.
You're absolutely right about side effects. I run a lipid referral center. Forty percent of my referrals are for statin intolerance. What we said in the guidelines was maximally tolerated statin therapy.
Dr Fuster: You said 40%. That's an impressive number.
Clyde, I read the 2013 cholesterol guidelines compared with the 2001 guidelines. There are significant changes, which I think are positive, starting with the high-risk patient. I don't have a problem with that. But I have a problem with the removal of lipid levels largely because of adherence issues. Patients like to know their target level, whether it's blood pressure or cholesterol. My hypothesis is that in the future, we'll use a combination of the 2001 and 2013 guidelines. I want to know your opinion.
Dr Yancy: I think the 2013 guidelines need to prevail because what's uniquely different about them is that they are driven by evidence. I think they really make it easier for the decision analysis. For the purposes of primary prevention, you can look at those individuals who are going to have a higher risk of an event and start an appropriate dose range of statin. It is an argument that is yet to be fulfilled that there is a single threshold LDL level that works for everyone. But I think it's pretty evident that for patients at risk, statin therapy reduces events. I fervently follow the path of the 2013 guidelines because I think it really reflects a direction of clinical practice that makes sense.
To respond to Jim, I hardly ever disagree with Jim, but actually, this does change my practice. I had largely put ezetimibe on the shelf. For me, I emphasize lifestyle change, advocating strongly about dietary intervention and statin as tolerated. Now if I have a secondary-prevention patient who, for whatever reason, is on an intermediate-intensity statin therapy, then I do have another option, particularly if I'm not comfortable with the threshold of the LDL-C level. Not treating to targets, but really trying to modify the events.
Dr Januzzi: But to be clear, the role of ezetimibe before IMPROVE-IT was to achieve some LDL-C lowering in patients who are maybe completely intolerant of statins, which in real-world practice is not a small issue. We do see this. I absolutely agree that proven therapies are the way to go, this is why we're not running directly to [proprotein convertase subtilisin-kexin type 9] PCSK9 inhibitors without an outcome trial.
I would say that in clinical cardiology we know that lower is better. The static from these trials of ezetimibe that didn't look so good I think was a distraction rather than being a valid signal. This really confirms what we expected, right?
Dr Watson: Right. When you looked in placebo-controlled trials, ezetimibe showed benefit, niacin showed benefit, and fibrate showed benefit. When you look on top of statin, nothing had.
Dr Yancy: That's the issue.
Dr Watson: You're exactly right. When we had someone who could not tolerate a statin, we went to ezetimibe because it did have data.
Dr Fuster: Michelle, how do you see all of this, ezetimibe coming into your life now?
Dr O 'Donoghue: Building on all the points that have just been raised, I'm starting to ask the question whether I should empirically be adding ezetimibe on top of a high-potency statin in my post-ACS patients. We're talking about targets for LDL-C, but IMPROVE-IT challenges the concept that there is a target or a threshold that we should aim for. It's all on a continuum.
Dr Watson: When we got to the very first panel meeting [for the guidelines], most of us were saying, I bet we're going to go to less than 70 mg/dL. We would have been wrong because 53 mg/dL was better.
Dr Januzzi: Let me challenge the guidelines, then. Why not just go with everything you've got, go all in therapeutically, to get a patient as low as possible?
Dr Watson: Two reasons. There were no data. Certainly, we're going to have a meeting to decide if anything needs to change with the guidelines. But remember, the guidelines did say if the clinician felt additional LDL-C lowering was necessary, addition of a nonstatin was fine. These data give us great evidence that addition of ezetimibe to max-tolerated statin is fine.
Dr Yancy: I actually think these data verify the guidelines because they already made accommodations for the individual patient who might need something beyond a statin. It's fortuitous that we now have evidence to support that kind of mind-set.
Dr Januzzi: I'm a biomarker guy. I have a hard time not looking at the LDL cholesterol. I suspect that the 2013 guidelines will shine as an example of the importance of aggressive care. But I do think the results of IMPROVE-IT indicate that knowing the gradient of risk, improving as we go lower with lower LDL-C targets, indicates some value to knowing where our patient sits.
Dr Yancy: The only pushback, I would say, is that the intent of IMPROVE-IT was to answer the question of whether or not ezetimibe plus simvastatin would lower events. It was not to test whether or not a threshold LDL-C of 50 mg/dL is the target. We have to be careful with that.
Dr Fuster: I want to ask Laura one question. We talk about levels, dosage and so forth, when, in fact, in our FREEDOM trial, comparing stents or bypass surgery in diabetic patients with coronary disease, actually 50% were not taking their drugs at 6 months. COURAGE showed the same thing. BARI 2D showed the same thing. Maybe we are very academically oriented here. The question is, not only should the patient take the drug, but does he? Then we can talk about everything else.
Dr Mauri: I agree. This trial was a strategy trial. Almost all the trials are strategy trials. As a trialist, LDL-C is not a perfect surrogate end point because, as you've pointed out, we have examples where we can lower LDL-C and it's not associated with better clinical outcomes. To me, the cleanest way and the simplest way to translate this to patient care is to talk about the strategy of the addition of a medication rather than shooting for a goal.
Dr Fuster: This is a great issue. The adherence is so poor. We don't pay much attention to it, but it's a reality.
Now we're going to go into surprises. We have four surprises, which we call negative studies on something that was supposed to be positive.
Aspirin in Primary Prevention
Let's begin by talking about aspirin. I'm a little tired of talking about aspirin. I've been talking about it for 40 years.
I was frankly surprised by this Japanese study[15,16] on low-dose aspirin. Basically, this is a study of 14 000 patients in Japan who were age 60 to 85 presenting with hypertension, dyslipidemia, or diabetes. They were recruited from all over Japan and followed for 6.5 years. They randomized these patients to enteric-coated aspirin 100 mg or no aspirin at all. The patients were treated appropriately for the risk factors that I mentioned.
The 5-year cumulative primary outcome event rate was exactly the same, whether you took aspirin or not. In one group it was 2.7% and 2.9% in the other group. There was a slight reduction in the myocardial infarction and [transient ischemic attacks] TIAs, but to a minimal degree. This is in patients at an age that already puts them at risk plus one additional risk factor; the role of aspirin appears to be somewhat negligible.
What do you think, Karol?
Dr Watson: I was surprised by this trial as well. I think there was a reduction in myocardial infarction and transient ischemic events, but there was a clear excess bleeding risk. I don't doubt that there is some population for whom the atherosclerotic cardiovascular disease risk is high enough and the bleeding risk low enough that we should use aspirin, but we don't know that group yet. We haven't figured it out.
I was struck that this population had 84% hypertension. We don't know how well controlled it was and if that increased the bleeding risk. But we can't say all primary-prevention patients take aspirin. We've shown several times that that doesn't work.
Dr Fuster: The Physicians' [Health] Study show only those at very high risk should take it because of the bleeding issue.
Dr Watson: The Physicians' Health Study included only male physicians. They did have a slightly increased risk of a stroke, decreased risk of an MI, but hard to know.
Dr Fuster: Clyde, what do you see of this aspirin business?
Dr Yancy: It's still very confusing.
Dr Fuster: Just say I believe, I don't believe it. This is subclinical disease for sure.
Dr Yancy: The question does become whether or not the atherosclerotic burden was already established and if the aspirin was started too late and would you move it upstream.
Dr Fuster: Michelle?
Dr O 'Donoghue: I have to say perhaps I wasn't surprised. Because I feel like the results are somewhat consistent with what we've seen to date. A marginal reduction in MI, but offset by an increased risk of bleeding in a patient population with a relatively low event rate.
Dr Januzzi: It's a question we've looked at before. The results are largely similar. Although MI was reduced, which we would hope to have seen, the balance of bleeding really leaned it to the negative.
Dr Mauri: Putting it into context of other areas, more and more we're thinking about withdrawing aspirin from strategies that include aspirin right now. Whether it's dual antiplatelet therapy or when patients need anticoagulation. It has been a great drug, and it still is in certain settings.
Dr Watson: In secondary prevention, it's good.
Dr Mauri: Yes, you're right. But in primary prevention, it's that trade-off.
Dr Fuster: How many people do you see as patients who never had any event and they come in on aspirin?
Dr Watson: Especially young women. I see so many and they're the least likely to benefit.
FACTOR 64: CTA in Patients with Diabetes
Dr Fuster: Now let's go into the second surprise. That is the so-called FACTOR-64 randomized clinical trial, which is a CT angiography trial performed in Utah. This study was presented by Dr Joseph Muhlestein. Basically 900 patients with type 1 or type 2 diabetes of at least 3 to 5 years' duration and without symptoms of coronary artery disease (only asymptomatic diabetic patients were recruited).
These patients were randomly assigned to a CT coronary angiogram (CTA) and or not to undergo CTA. Then if the CT showed disease, they were treated accordingly and it was like an intention to treat.
The bottom line is that there was no difference at all in any of the events they looked at, whether you do an angiogram or not. To me, this is a little bit surprising because there are interesting data in this study. For example, 20% had some degree of moderate to severe stenotic lesions in the coronary arteries.
My interpretation of this is that it's a little bit like the COURAGE trial or any of these trials of medical therapy. But I'd like to know how you react. These are diabetic patients. They were completely asymptomatic, and CT angiography showed disease in a significant number of coronary arteries, but it doesn't make any difference. The follow-up was reasonably long.
What do you think?
Dr O'Donoghue: From my perspective, it reaffirms that for a patient who's asymptomatic even if they have established coronary artery disease, stenting that lesion is not going to reduce deaths, it's not going to reduce the risk of MI. I think that coronary artery calcium scoring, as well as a CTA, are good for risk stratification, but I think the question there is, What do you do with the information? What kind of aggressive risk factor modification should you employ? It doesn't seem that revascularization is really the answer.
Dr Fuster: Jim?
Dr Januzzi: To me this was one of the most surprising results of the trials that were presented. Because it speaks to the fact that knowing the patient has severe disease does not necessarily change outcomes. But on the other hand, if you look at the absolute event rates, they were actually quite low, which speaks to the power of good medical management.
In the Intermountain Medical Center system, they did a remarkable job of mitigating risk factors. Even at the time of randomization, their lipids were well-controlled, their glycohemoglobins were well controlled. It shows the quality of care that these patients received.
Dr Watson: I've got to say I wasn't surprised by these data because it's very COURAGE-like, as you mentioned. Knowing that there is anatomic disease just tells you that you really need to double down on risk-factor reduction.
Dr Fuster: Absolutely. What do you think?
Dr Yancy: This completely validates medical therapy for what is a systemic illness. We have this knee-jerk response. We see an obstructive lesion and we should do something about it. But the burden of disease is really what's most important.
Dr Fuster: I think it's a good lesson. What have you seen, Laura?
Dr Mauri: I think we still need more of a functional assessment to be able to know whether it's worth going forward with revascularization.
Dr Fuster: They didn't have functional assessment. It was all anatomical.
Dr Mauri: Right. It's interesting because there are now CT strategies that let you look at that.
Dr Watson: But even a functional assessment, I would argue medical therapy will in the absence of functional limitation.
Dr Mauri: But it may select a higher-risk group.
Losartan vs Atenolol in Patients with Marfan Syndrome
Dr Fuster: Let's continue with the surprises.
Atenolol vs losartan in children and young adults with Marfan syndrome.[19,20] A study from the United States that involved with a large number of patients, about 600. Dr Ronald Lacro presented the paper. This paper had great expectations because of the original registry data from Northern Europe showing that in patients with Marfan, the use of losartan could prevent the progressive dilatation of the aorta.
There were 600 patients. They really looked not only over a 3-year period whether the aorta dilated progressively, but they looked at aortic dissection and other events (including death and aortic-root surgery). The results were absolutely negative. One group was treated with atenolol. I think the highest dose of atenolol was 250 mg (a maximum dose of 4.0 mg/kg per day not to exceed a total dose of 250 mg). And the losartan dose was a good dose (maximum dose of 1.4 mg/kg per day not to exceed a total dose of 100 mg). I don't think there was a problem with the dose. But it's disappointing when we see so many of the patients with dilated aortas, which are not Marfan. This is going to change my practice, I was giving losartan to all of my patients with any slight dilatation of the aorta.
What do you think, Laura?
Dr Mauri: I think it's too bad. It was obviously a very good study, and powered, so it's disappointing.
Dr Januzzi: The basic science would have suggested losartan would have been better. In fact, the basic science also suggested that atenolol might have been worse. There were some suggestions it might actually be. But Myron Wheat started giving beta-blockers in aortic dissection a very long time ago for a reason. It brings us back to the historical precedent of using beta-blockade in this setting. It's a reassuring finding that the many, many patients out there who are on beta-blockers are on a therapy that's a reasonable choice.
Dr O 'Donoghue: I would just echo what Jim said, that at least we know that beta-blockers are reasonable in this setting.
Dr Fuster: Except there's no trial. There are no trials that show a benefit for beta-blockers in Marfan. That is why when this drug came along there was great hope. We give beta-blockers for the [diastolic pressure/diastolic time] DP/DT and blood pressure and so forth, but the reality is that there are no trials. What do you think?
Dr Watson: I agree. Very little data for either therapy. The good news is there was no penalty that you paid for being on losartan.
Dr Yancy: But the other thing is that this is a population that really needs something that will dramatically change the natural history of their disease. That's part of the disappointment. But the other part is that even when something is biologically plausible and is preceded by observational data, the benefit of a randomized control trial is that it answers an important question; this was with the positive comparator.
Dr Fuster: It's interesting because the other two studies we presented, no aspirin, good, no CT angiograms, good. But here, we are left with frustration.
CABG With or Without Mitral Repair in Ischemic MR
Dr Fuster: Let me show you the next surprise. Surgical treatment of moderate ischemic mitral regurgitation.[21,22] (This is like an examination for the board. We have all sorts of cardiac diseases at this meeting.)
I have some problems with this study, but let's see what you think. There has been a significant drive toward mitral-valve repair, with or without bypass surgery. This paper turns this around and examines bypass surgery with or without mitral repair. It was presented by Dr Robert Michler at Montefiore.
They randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus mitral valve repair. Basically, there was no difference in the primary end point of left ventricular and systolic volume index, a measure of ventricular remodeling at 1 year.
My problem is how can you judge this with only one year of follow-up on a patient with valvular heart disease? I would like to see 5 years of follow-up.
What is your opinion, Laura?
Dr Mauri: We looked at percutaneous mitral-valve repair in a different patient population, compared with surgical. We did see changes in echo parameters like left ventricular systolic dimension within 1 year.
Dr Fuster: In favor of repair?
Dr Mauri: They both improved, both arms, although more so with the surgical intervention. I think it can be seen [within a year]. But it's not the same patient population.
Dr Yancy: Val, let me give you another perspective here. This was echo-verified, at least moderate MR. That part of the substrate was homogenous, if you will, by contemporary criteria. One would argue that for those that have moderate MR that are undergoing bypass surgery, there should have been some evidence that repair of the valve would have made a difference in the 12-month period of time. I think we have to acknowledge that.
On the other hand, long-term follow-up would be interesting. But the 1-year data cannot be dismissed, because it really does say that for the price you pay, the extra pump time, the extra bleeding, which was well captured in the paper, one has to balance that price with the absence of structural benefit at the end of a year.
Dr Watson: That's my main problem with the study is you did pay a penalty for doing this therapy. You had increase in strokes and more pump time and adverse events. If there were no penalty, I would agree. I'd be happy to see it followed out longer.
Dr Yancy: A lot of our surgical colleagues like to fix everything they can when they're there for empiric reasons, but not driven by a data set. I wonder if this will change behavior.
Dr Januzzi: That's the strength of the study, right? Randomized controlled trials are unfortunately fairly rare in cardiac surgery. In this regard, the investigators should be congratulated.
Dr Yancy: Absolutely.
Dr Januzzi: The improvement in mitral regurgitation in the CABG-only arm was actually a lot more than has been seen in some other studies too. I think that the decision to fix a valve at this point, much like everything we do in medicine, is an individualized decision rather than a one-size-fits-all.
Dr Fuster: I have to read the paper carefully, but with moderate MR, you don't know what you're dealing with.
Dr Januzzi: That's the other thing. When we're in the operating room with a patient under anesthesia, moderate MR, a lot of things change when the patient's asleep.
Dr O'Donoghue: The point is well taken that we can't ignore the signal that we've seen toward harm. I think it has given me a fair degree of pause when thinking about patients and whether or not mitral valve repair should be more routinely performed.
Dr Fuster: You make a good point, because I was disappointed that there was only one-year follow-up, but even during that year, there are a number of problems in the surgical patients with mitral repair, which I think one has to take into account and to follow these more carefully.
Dr Fuster: I'd like to finish with five curiosities, one after the other. As we know, time is of the essence in acute myocardial infarction, but the problem is that many patients delay seeking help. This was looked at in the STEMI ACCELERATOR study. Many institutions participated. We all know that one of the great problems is the time to physician contact. We have tried to reduce delays once the physician knows about the patient, but this study shows that we need to have a better system. We probably need an educational campaign.
There are many people who are afraid to call a doctor when they have chest pain because they are afraid that it will turn out to be nothing and they will be embarrassed. I have never seen a patient who turned out to have nothing and thought "why did they bother coming in?" I don't know any physician who would think that. Patients need to know that we physicians never think like that. Is that right?
Dr Mauri: Exactly right.
AVOID: Oxygen in STEMI
Dr Fuster: This is one of the issues that has to be addressed. Now curiosity number two.
This is a good one. Oxygen in acute myocardial infarction. Everybody wears a mask.
Dr Januzzi: They look sicker when they're wearing oxygen, right?
Dr Fuster: This is the AVOID study done in Melbourne, Australia. Dr Dion Stub presented it. This is based on the concept that perhaps oxygen can be detrimental to your health when you don't need it.
There were 638 patients with normal oxygen saturation following MI. If they were randomized to the oxygen mask, they ended up with more problems. Supplemental oxygen therapy in patients with STEMI but without hypoxia increased myocardial injury, recurrent myocardial infarction, and major cardiac arrhythmia and was associated with larger myocardial infarct size assessed at 6 months. That's why they look sicker.
Dr Januzzi: Because they are sicker, actually.
Dr Fuster: This is a great lesson.
Dr Yancy: They did give them 8 L per minute. It was a big dose. Keep that in mind, it's a big dose.
Dr Fuster: But it's always funny to see hospital staff giving oxygen to somebody with normal oxygen.
Dr Watson: We know that oxidation, superoxide, things like that are not good. What we're trying to do with that, I'm not sure.
Dr Yancy: We may be back to choosing wisely again.
INHERIT: RAS Blockade in HCM
Dr Fuster: The next one is somewhat disappointing. It's the INHERIT study. The inhibition of the renin angiotensin system in hypertrophic cardiomyopathy [HCM] and the effect on hypertrophy in fibrosis. They basically follow up with MRI.
We've always seen that the fibrotic phenomenon can be, in a way, counteracted by the use of, in this case, losartan, and didn't touch it. Are you surprised?
Dr Mauri: I think it's like Clyde said earlier, even if we think it should work, it doesn't always work. We have to go back and figure out why.
Dr Fuster: Maybe you need 10 years.
Dr Watson: It may be. But within the angiotensin aldosterone system, we've seen an aldosterone antagonist didn't work to prevent fibrosis.
Dr Fuster: This is the problem. When you look at the whole fibrosis concept, it's really very hard to come up with any meaningful progress at this time.
Dr Yancy: We need a new direction.
WOSCOPS and Endocarditis
Dr Fuster: Still two things to go. You remember the West of Scotland Coronary Prevention study? Twenty years ago. You remember these were patients with hypercholesterolemia. The patients were started with pravastatin. At that time, I think it was at 5 years of follow-up, there was a 13% improvement on the primary end points. At 20 years, it's 27%; the curves continue to separate. It tells you the importance of long-term follow-up studies. This was quite fascinating.
Dr Yancy: What was the LDL level in that study?
Dr Watson: They started at 190 mg/dL, I believe.
Dr Fuster: To finish, this is something we have to think about. You've probably thought many times, when you have a patient with a dental problem who has a prosthetic valve. You say, don't do anything because this isn't a problem. Let me tell you the problem.
In the UK these NICE guidelines came in March of 2008. I remember being shocked, because they said that you don't need to do anything. In the majority of patients, we gave antibiotic prophylaxis. This was much of 2008.
This study from Britain followed up to see what happened from that moment. The mean prescriptions for prophylactic antibiotics in the UK dropped from over 10 000 per month between 2004 and 2008 to 2000 between April 2008 and March 2013. From 10 000 to 2000. This matches exactly with the progressive increase of infective endocarditis; they saw 34 more cases per month.
Dr Watson: The problem is, there's very little really high-quality data on either side of it, so people erred on the side of let's back off. But I think we backed off too much.
Dr Yancy: I was like Val. It was really hard for me to embrace those guidelines fervently. I just follow too many people who are at risk.
Dr O'Donoghue: For our patients who were so used to taking antibiotics in that setting, it took a lot of convincing.
Dr Watson: We did finally convince them. Now are we going to tell them?
Dr Januzzi: It took years to get that momentum going to not treat.
Dr Yancy: But once again, the benefit of evidence.
Dr Watson: We still need the randomized control trial.
Dr Mauri: I think this tells us that sometimes we don't have the evidence, but it's like seat belts, where it just makes sense.
Dr Yancy: I think I know what I'm going to do tomorrow.
Dr Fuster: This still has to be studied very carefully because the fact that these observations are not necessarily a cause and effect, but it seems to me that that's probably the case.
Dr Fuster: This is really a summary of what we learned in the last few days. It's quite interesting. I think that the DAPT trial is probably my number one, I think IMPROVE-IT was also very impressive. Then the issue of stents, we have to wait with these biodegradable-polymer stents. But I was impressed by the trials that were negative for aspirin, CT angiography, and the Marfan syndrome study. This was something.
From among my five curiosities, I think the infective endocarditis one is something we have to revisit.
I really appreciate being here for at least an hour. It was fun. Thank you very much to all of you.
News stories on some of the trials discussed
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Cite this: The Cardiology Show From AHA 2014 With Dr Valentin Fuster - Medscape - Nov 19, 2014.