Moderator: Valentin Fuster, MD, PhD, Panelists: Anne B Curtis, MD, Pamela S Douglas, MD, MACC, Sanjit S Jolly, MD, MSc, Neil E Moat, MBBS, FRCS, Prediman K Shah, MD

Disclosures

March 17, 2015

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Editor's Note: From the American College of Cardiology 2015 Scientific Sessions in sunny San Diego, Dr Fuster reviews CT angiography in PROMISE and SCOT-HEART, ticagrelor in PEGASUS, the injectable PSCK9 inhibitors, and a range of interventional cardiology trials (MATRIX, TOTAL, PARTNER). However, the study that packs the biggest punch is one on weight loss in patients with atrial fibrillation.

Introductions

Valentin Fuster, MD: Hi, I'm Valentin Fuster from New York. We are in the scientific sessions of the American College of Cardiology. We are in sunny San Diego, but I haven't had a chance to get into a swimming suit and go out. They didn't allow me to do so, because I'm working very hard. Speaking of the sun, we have sunny people here today. An outstanding group who are going to discuss a number of subjects.

Let me introduce: Dr Anne Curtis to my right is a distinguished professor, the Charles and Mary Bauer Professor, and chair of the department of medicine at the University of Buffalo.

Dr PK Shah is a great friend. At Cedar Sinai he is the director, Oppenheimer Atherosclerosis Research Center, Atherosclerosis Treatment and Prevention Center, at Cedars-Sinai Heart Institute in Los Angeles, and he is professor of medicine at the David Geffen School of Medicine, at the University of California, Los Angeles.

Next is a surgeon who smiles (I'm not saying anything against surgeons), Dr Neil Moat. He is the director of the TCV program at the Royal Brompton & Harefield at Foundation Trust, London, in the United Kingdom.

Then we have Dr Pamela Douglas, professor of research in cardiovascular disease at Duke Clinical Research Institute in Durham, North Carolina.

Finally, to my left is Dr Sanjit Jolly, associate professor, department of medicine, McMaster University, Hamilton, Ontario. He is an interventionalist, so watch him.

We have a lot to cover, so we really have to get moving. There were a number of interesting studies presented in this meeting. Some were diagnostic (the first one that we are going to discuss), some dealt with therapy, some dealt with intervention, so let's try to do the best we can over the next hour.

PROMISE: Anatomic vs Functional Testing in Symptomatic Patients with Suspected CAD

The first study that we are going to discuss is the PROMISE trial.[1,2] The full title of the New England Journal of Medicine paper is "Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease." We have the PI, Dr Pamela Douglas, with us. I told her she cannot speak unless we ask a question.

It is a very interesting study, because as you know, many patients present to us with symptoms of coronary artery disease, but often we are not entirely certain what diagnostic test to use. One of the approaches for noninvasive testing is exercise testing of one modality or another. Another possibility is [computed tomography] CT angiography [CTA]. In the past, we thought that CT angiography perhaps was too cumbersome, too expensive, and it confers some degree of radiation on the patient. Dr Douglas decided to test these two possibilities in over 10,000 symptomatic patients from 193 sites in North America. One group was tested anatomically with the use of coronary CT angiography, and the other group with exercise testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or measured procedural complication, and the secondary end point was invasive cardiac catheterization that didn't show obstruction and the degree of radiation exposure. Interestingly 52% of the patients were women. This is quite fascinating, because in most of the studies we don't have that many women. The mean age was 60 years, and over a median follow-up of about 25 months, the primary end point occurred in 3.3% in the anatomic group vs 3% of the functional testing group. No difference in terms of the end points.

I would have predicted that the rate of revascularization would be high, but actually in the first 90 days it was only 6.2% in the group that had CTA vs 3.2% in the group that was noninvasively tested with exercise.

A final issue that I think is important is the radiation exposure. Overall, there was less radiation in the CTA group than in the stress-testing group, but of course this depends on the kind of exercise test you do. Obviously if you do nuclear stress testing, there is more radiation than with CTA, but if you do stress ECG or stress echo there is no radiation.

The conclusion of the study is that in symptomatic patients with suspected coronary artery disease who required noninvasive testing, a strategy of initial CTA as compared with functional testing did not improve clinical outcomes over a median follow-up of 2 years. I would like to finish by saying that Dr Daniel Mark, also from Duke, presented the related economic data, and this is where I was surprised. I thought with CT angiography, there would be more testing and more revascularization, but the economics were practically the same for the two approaches (anatomical vs functional). What do we do with our next patient with chest pain if we don't know if there is angina or not?

What Test Would You Choose?

Dr Fuster: What do you think, Anne? How do you react to this study?

Anne B Curtis, MD: It sounds to me like you've got options. Some centers favor CT angiography. Others favor the stress-echo approach. At first glance, I would say that they are fairly equivalent and we can go either way, it doesn't sound like the PROMISE data strongly favor one or the other.

Dr Fuster: PK, if you had some chest discomfort and you didn't know if it was cardiac, what stress test would you choose for yourself?

Prediman K Shah, MD: Personally, if I had no contraindication for CT angiography, I would probably go for it because it would give me a definitive answer as to whether I have obstructive disease or not. If I have nonobstructive disease, risk-factor modification might be enhanced, so that is a personal point of view.

Dr Fuster: Neil, what test would you choose?

Neil E Moat, MBBS, FRCS: I think I would have functional testing.

Dr Fuster: You don't want to know?

Dr Moat: No, I'd like to know if I have functional ischemia, because I'm not sure that CT angiography really gives you precise enough information on whether the lesion is flow limiting or whether the plaque is unstable, so I think if I had symptoms suggestive of angina, I would rather have a functional test.

Dr Fuster: Sanjit?

Sanjit S Jolly, MD, MSc: As an interventionalist, my preference is usually anatomic imaging, because we see a lot of patients come to the cath lab who have had an abnormal functional test and they have normal coronaries. Especially with low-risk patients, perhaps we're putting them through risk needlessly.

Dr Fuster: Anne, there is another question here: radiation vs no radiation, what would you do?

Dr Curtis: Honestly, many of these patients are going to turn out not to have much of anything. If it were me personally I would probably prefer the CT angio because then I would know what the anatomy looks like. With a functional test you can't always tell what that means anatomically. I like the idea that I would know structurally what is wrong.

Dr Fuster: If I thought it unlikely to be angina, I would do stress testing, but if I suspected that it really is angina, then I would prefer CT angiogram. Pamela, did you come from CT angio, if I recall correctly?

Pamela S Douglas, MD, MACC: No, I've never done CT. I'm an echocardiographer. I would probably do a stress test because I think the functional information is very important if you have a patient that can exercise. Now, if you have a patient that can't exercise, who doesn't have a readable ECG, who can't get on the treadmill, then I think the CTA may be the way to go. So I'm sort of in the middle.

Dr Fuster: The functional status of the coronary system is important. This is something that we cannot get away from, but there is room for clinical judgment because there are people who are patient enough to go step by step, but there are others who want to know right away. The anatomy obviously is something that you see directly with CTA. Are you in agreement, PK?

Dr Shah: I think the other collateral benefit of doing the CT angio is after having excluded obstructive disease if you have nonobstructive disease, you know you have atherosclerosis and are at future risk, so that might motivate you to follow risk-factor modification quite aggressively. Whereas a negative stress test would not reassure me that there is nonobstructive atherosclerosis.

Dr Fuster: That is a good point. This study had a relatively short follow-up. It's less than 3 years, but I would want to know what's going to happen in 5 or 10 years. Stress testing will give you some information, but I am impatient and I would want to know more about my future risk. I think we have to individualize the decision. You cannot say one particular test is for everybody. Pam?

Dr Douglas: I would agree, and I would also say it is not just about individualizing for the patient. It's also individualizing for the expertise in the center where the patient is being tested. If you have superb CT and maybe the functional labs are not as good or vice versa, then you may want to lean toward whichever test will yield the most reliable information.

Dr Fuster: I thought the radiation levels in your study were a little bit high compared with the type of radiation that at least we see in some of the CT equipment that we have in academic institutions.

Dr Douglas: Yes, but PROMISE is a community-based, pragmatic trial. A lot of the people had older equipment that doesn't have the gating sequences we see on newer equipment. PROMISE really represents the practice in the community now as opposed to practice in a high-end academic center or a regional referral center where people have spent time getting their radiation levels down and tweaking their scan protocols.

SCOT-HEART: CT Angiography in Patients With Suspected Angina Due to CAD

Dr Fuster: Another CT study was presented at this meeting, the SCOT-HEART study.[3,4] Basically, it's a study carried out in Scotland with over 4000 patients in 12 clinics. The patients were randomized to CT angiography or standard care, basically whatever the doctor wanted to do. It was not very precise in terms of what was done in the control arm. That said, in about 25% of patients the initial diagnosis was clarified from either no coronary disease to coronary disease or vice versa on the basis of CTA.

When you see something, then you begin to think about what to do, whereas with stress testing you are still a little bit up in the air. My summary of both PROMISE and SCOT-HEART is that judgment still has to come into play. If I suspect that the patient in front of me does not have angina. I would do stress testing. I wouldn't do a CT angiogram. If I feel that the patient has angina, then I may do a stress test to get their functional status, and then do a CT angiogram to know the anatomy because that predicts the future. If I know the patient has angina, I don't necessarily do an angiogram right away. I would like to know functionally what region and so forth, and then I may go to the angiogram. Would you like to discuss this, Anne?

Dr Curtis: It's always a judgment call. When I take care of patients, my ideal would be I do one test and I get the answer. So if you have somebody who has very typical angina and has advanced symptoms, then the first thing you want to do is an angiogram and take care of the problem. I find it a bit of a disappointment if I do a stress test and then I have to do a nuclear test, and then I wind up doing something else. I feel like I've gone in the wrong direction, but that is why we are cardiologists. We need to look at the findings and try to sort them out.

Dr Fuster: When we think it is angina, the stress test is more to quantify the degree of ischemia, which is quite important in terms of what you are going to do next. I don't think we can say I will do one test or the other. You end up perhaps not doing a CT angiogram and going directly to the coronary angiogram if you have to intervene. PK?

Dr Shah: Even that might change if fractional flow reserve [FFR] by CT turns out to be a reliable, reproducible test. Then you might get functional information as well as anatomic information from the CT, but that remains to be seen. I agree with you that when the patient has a very low likelihood of obstructive disease based on your overall assessment, then it is okay to do a stress test. But if there is a chance, then I want to know for sure whether there is disease and [whether it is] obstructive or nonobstructive.

Dr Fuster: And if you are convinced that this is angina, you go directly to a regular angiogram, not CTA?

Dr Shah: Yes, because that combines a therapeutic and a diagnostic procedure.

Dr Fuster: The patients in PROMISE were relatively low risk. Would you agree, Pam?

Dr Douglas: It's hard to say. In PROMISE, two-thirds of the patients were over the atherosclerotic cardiovascular disease [ASCVD] cut point of 7.5% risk. The pretest probability of obstructive disease was over 50%. They had an average of two and a half risk factors, middle-aged, symptomatic.

Dr Fuster: If you have very low risk, you do stress testing. If you are intermediate risk, you do a CT angiogram, and if you have high risk you do an angiogram. Anne?

Dr Curtis: I think that makes a lot of sense.

Dr Shah: I think that is a reasonable strategy.

Dr Moat: I think the study suggests that you have benefit when doing both functional and CT angiogram because I think that is what happened in the CT group. They also had functional testing.

Dr Douglas: In SCOT-HEART, but not in PROMISE.

Dr Moat: The interesting finding from SCOT-HEART is that there was a suggestion (almost statistically significant at 18 months) of a reduction in the rate of MI in the patients who had CT angiogram and functional testing compared with functional testing alone. So if it were me in the intermediate risk group, I would like to have both.

Dr Fuster: Pam, would you agree with my low-risk, medium-risk, high-risk strategy?

Dr Douglas: It's interesting: the British guidelines for stable chest pain[5] recommend coronary artery calcification [testing] for patients with a likelihood of <30%, functional testing for those 30% and 60%, and going directly to the cath lab for patients with over 60% likelihood of having CAD. Just the opposite of what you propose in the low- to intermediate-risk group. To me that makes some sense. If you have a calcium score of zero, you are pretty unlikely to have anything, so that excludes the low-risk people very quickly.

The concept of parsing out low-, medium-, and high-risk patients to different tests is very attractive.

Dr Jolly: I would agree with Dr Fuster and it seems to make economic sense. If you have a 40-year-old woman with a very low pretest probability, put her on the treadmill to exclude. Then as an interventionalist, I like the anatomic information in the mid-risk patients when they come to the cath lab. And going straight to angio for high risk because these are patients we want to help right away.

Dr Fuster: Clinical judgment is the name of the game. Wonderful.

PEGASUS: Prevention of CV Events in Patients with Prior MI Using Ticagrelor vs Placebo

Dr Fuster: Let's now move from diagnosis into therapy. This is the study on the long-term use of ticagrelor in patients with prior myocardial infarction. It was presented by Dr Marc Sabatine from the Brigham and Women's Hospital in Boston.[6,7] This is the so-called PEGASUS-TIMI 54 study.

As background, the practice guidelines from the United States and Europe currently recommend P2Y12-receptor antagonists for up to 1 year after myocardial infarction. There is nothing specific about what to do after that year. The PEGASUS investigators recruited 21,000 patients from 31 countries who had an MI within the previous 3 years, and the randomization was ticagrelor at the dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. There was some concern about bleeding, and that is why the lower dose was also tested. All of the patients received low-dose aspirin, and the control group was low-dose aspirin only. They followed these patients for 33 months, and the primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke, and the primary safety end point was TIMI major bleeding.

The result for the primary efficacy end point was 7.85% in the group that received 90 mg of ticagrelor, 7.77% in the group that received 60 mg of ticagrelor, and 9.04% in the placebo group. So the absolute benefit was about 1.2%.

The rates of TIMI major bleeding were higher in the ticagrelor group: 2.6% for 90-mg bid dose, 2.3% with the 60-mg bid dose, vs 1.06% in the placebo group. A difference in bleeding of between 1.3% and 1.6%. When you look at both figures, I have a problem. This was major bleeding. It's true that the patients didn't die of the bleeding, but the amount of bleeding was very significant. Their conclusion: in patients within 1 to 3 years of MI, treatment with ticagrelor significantly reduced the incidence of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. Sanjit, how do you react to all of this? There are two things in the balance here.

Dr Jolly: It makes sense that longer duration of antiplatelet therapy is going to reduce myocardial infarction. And it also makes sense that it increases bleeding. The question is, what is the trade-off? And clearly we don't use aspirin and clopidogrel long term, for the most part, post-MI. There was some debate about stented patients. These data allow for judgment. If you have a high-risk patient, I would be inclined to treat them with ticagrelor. If you have a low-risk patient you can certainly use judgment. If you have a patient at high risk of bleeding, I would certainly not use long-term ticagrelor because in fact you may do harm.

Dr Fuster: I think that makes sense. Pamela?

Dr Douglas: I think it depends on bleeding risk. The benefit is small, and it is the same actually at the lower dose when the bleeding risk is lower. The biggest take-home message for me from this trial is to drop your dose of ticagrelor; the lower dose appears to be equally effective but perhaps safer.

Dr Fuster: I have a question here about economics. We know that 80% of MIs take place in countries that are medium or low income, and you are dealing with a drug that is not cheap. Clopidogrel was not tested in this study. My question is if we are going for long-term therapy because the risk is high (assuming we agree with that), is ticagrelor the only approach?

Dr Douglas: I don't think ticagrelor is the only approach, and in fact, the study tells us that we don't have a mandate to treat these patients with ticagrelor. When you see the risks and benefits, the risk of giving the therapy is very equivalent to the benefit you are going to get. Are you going to do it?

Dr Fuster: Similarly for clopidogrel, because in CHARISMA[8] the combination worked, but it was a secondary end point. What do you think, PK?

Dr Shah: Doubling the risk of bleeding—even at the lower dose of ticagrelor, there was a doubling, and at the higher dose it was slightly more than doubling the risk of major bleeding—coupled with very small absolute risk reduction does not make a persuasive case for it as far as I'm concerned.

Dr Fuster: What is your view as a surgeon?

Dr Moat: Well I think this is like the first two trials we discussed. It shows that clinical judgment is still really important. If you have a younger patient with a very low risk of bleeding who you think has a high risk of further MI, you might go for the ticagrelor for long term. In the elderly patient I would suggest that you would probably not. I can't remember whether they did an age-related subanalysis in the study and whether the bleeding risk was higher in the elderly patients.

Dr Douglas: They did a subgroup analysis by age and there was no difference in bleeding.

Dr Fuster: I tend to agree with all of you. There is a trend for benefit in patients at high risk who are treated long term, as we saw in the DAPT study.[9] But the trend is not high enough for me to say that I would treat all of my patients with long-term DAPT. The economic issue is significant, maybe not for a country like the US, but certainly it is something to take into account. I think it is an interesting study, but I would be cautious in running too far with the data as if we have the answer for all. Do you agree with that?

Dr Jolly: I think it would have been different had we seen a mortality reduction.

Dr Fuster: All-cause mortality was no different.

Dr Jolly: That would have tipped the balance for me.

OSLER: Effect of the PCSK9 Inhibitor Evolocumab on CV Outcomes

Dr Fuster: Since we are now treating patients medically, we have another good study, also presented by Marc Sabatine. I hope he went home to rest. This one is the efficacy and safety of evolocumab.[10,11] I always have problems pronouncing this—do you have problems pronouncing all of these PCSK9 inhibitors?

Dr Douglas: Evolocumab. I've been practicing.

Dr Shah: It will be named something different that will be much easier to pronounce [Repatha, Amgen].

Dr Fuster: The use of these drugs to reduce lipids and cardiovascular events is a fascinating story. It has to do with LDL receptors, and there is an inhibitor of the receptor that is called PCSK9 that prevents the LDL cholesterol from getting to the liver cells. These drugs use an antibody that blocks PCSK9 and allows the LDL-C to enter into the liver. It's very clever, and there have been a lot of short-term studies over the past 2 or 3 years using this approach. Well, these researchers pooled two of these short-term studies and extended the analysis for a longer period of time.

These were two open-label, randomized trials in which nearly 4500 patients were enrolled in 190 centers who had completed phase 2 or 3 so-called parent trials on the use of evolocumab. The patients were randomized in a 2:1 ratio to receive either the test drug 140 mg every 2 weeks or 420 mg subcutaneously once a month plus standard therapy or to standard therapy alone, and then the patients were followed with the assessment of lipids; safety and adjudicated cardiovascular events included death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure.

Both studies were combined in one. Compared with the standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%. This is not new. We already knew that from the previous studies. The adverse events occurred with similar frequency in the two groups, but I have some concerns, because 69% of patients [in the treatment group] reported adverse events and 64% of the standard-therapy group. I don't know if these patients were followed every hour to account for all these events. It is a very high rate, and we should talk about it. There was some concern about cognitive function that seemed to particularly affect the group with the test drug, although it was less than 1% of patients.

In terms of efficacy, the rate of cardiovascular events at 1 year was reduced from 2.1% in the standard group to 0.95% in the evolocumab group, which was statistically significant. Summarizing in the course of 1 year of therapy: the use of evolocumab plus standard therapy as compared with standard therapy alone significantly reduced the LDL-cholesterol level and reduced the incidence of cardiovascular events in a prespecified exploratory analysis. PK, what do you think?

Dr Shah: These data are pretty supportive of what has been published to date from smaller studies, that these inhibitors are extremely potent in reducing LDL-cholesterol levels and really represent the next advance beyond the statins for LDL-C lowering. From this particular study, there is a small worrisome signal about cognitive malfunction from 0.3% to 0.9%. It's still pretty small and may just be noise, but with a drug that has to be taken lifelong, even these small differences need to be followed over a longer period of time so that we can be assured that there is not a liability for massive reduction in LDL cholesterol. Very promising, but we need to be cautious long term, and we need more long-term data.

Dr Fuster: Anne, what do you think?

Dr Curtis: I agree. If [in the] short term a few patients have problems like that, would it be a higher percentage of patients if they got treated with those drugs longer? In this study, were the patients also on statins or is this instead of statins?

Dr Douglas: Not all, but most were on statins.

Dr Curtis: We all have patients who can't take statins for various reasons, and there haven't been a lot of good alternatives, so if we have a new class of drugs that shows promise for that, I think that is an advance that we have been looking for.

Dr Fuster: It's exciting, but Pamela, I look at the side effects and it's troublesome, 69% in the evolocumab group but also 64% in the standard-therapy group. The rate of serious adverse events was 7.5% in both groups, muscle-related 6.4%, neurocognitive 0.9%, injection-site 4.3%, arthralgias, headaches, limb pain, fatigue. These patients were followed carefully—if they had any problems, it got tracked.

Dr Shah: We've been participating in some of these trials, and patients are followed very closely, and every little symptom that occurs is recorded as a potential adverse event.

Dr Douglas: And that is the right way to do a trial. Every adverse event should be reported and classified, and that is why you have the placebo-control arm. There's a couple of questions about these therapies. One is the long-term, truly long-term safety. The neurocognitive side effects have not been analyzed in a very formal, adjudicated way. I know that is coming from this research team eventually in other studies, but it really needs to be done with quantitative surveys and so on. So the safety is outstanding. They had over 700 patients who had an LDL-C of under 25 mg/dL, which is strikingly low, and what that does to you over the long term is a question. But I think there is also the question on the other side. Do we need statins? Obviously, if you can't take statins, this looks like it's going to turn out to be a great alternative, but potentially the PCSK9 inhibitors have fewer side effects than statins. The myalgias are less, and I know people say, "But it's an injection." But one shot a month instead of remembering to take a pill every day. That wouldn't bother me.

Dr Fuster: One of the problems is medication adherence, but with an injection once a month, I think adherence would improve.

Dr Shah: It is actually more than one injection. Most of the patients require two to three injections at the same time because the volume of injectate is limited, so in order to get a larger amount of drug you have to split it over two to three injections. Some of my patients (in the PCSK9-inhibitor trials) needed three injections at the same time; three injections is a bit of an issue. But that is a practical issue that they might be able to solve by concentrating the drug and using only one syringe.

Dr Fuster: The low level of cholesterol didn't make a difference, but we need cholesterol to think. Cholesterol is necessary in the membrane of cells, and all of us have experienced that when you drop the cholesterol level significantly with statins, you begin to get side effects of one kind or another. I don't think we need to go to these very low cholesterol levels.

Dr Moat: Valentin, I think the neurocognitive issues are important because certainly there has been a lot of work in cardiac surgery obviously looking at neurocognitive issues, and once you start looking more closely with a very qualitative approach, as Pamela mentioned, it is likely that the real incidence is probably going to be much higher than 1%, so that does worry me a little bit. These things may be having a significant cognitive effect.

Dr Fuster: I think we are going to learn very quickly about this, because there are actually two or three more studies being done in high-risk patients and for a longer period of time, and there are two other drugs of the same class. This field is moving very rapidly, and it's very exciting. Sanjit, I will give you the last word, are you excited?

Dr Jolly: I am, but I think the neurocognitive issue is an important issue.

Dr Fuster: An interventionalist is excited about a drug. I think this is a great accomplishment.

Dr Shah: I just want to make one important point, and that is about patients who are dependent on LDL apheresis. For them this is a potentially a game changer because the quality-of-life impact of LDL apheresis is significant. One of the first patients I put on a PCSK9 inhibitor managed to get completely off LDL apheresis and had a huge quality-of-life improvement. For that particular group of patients, these drugs could be a godsend.

Dr Fuster: I have a patient who goes for plasmapheresis every 2 weeks who called me about 2 hours ago because they heard about this drug on the radio, but they were concerned about the cognitive effects. We have to be very careful not to blow these out of proportion. I think this is an interesting study.

LEGACY: Long-Term Effect of Goal Directed Weight Management on AF

Dr Fuster: This next one is the most striking data at this meeting. It is obesity and atrial fibrillation.

This is a very well-done study from Adelaide in Australia, called the LEGACY study (Long-term Effects of Goal-directed Weight Management in an Atrial Fibrillation Cohort), a long-term follow-up.[12,13] It was presented by Dr Rajeev Pathak. It is a longitudinal study, so this is not a randomized study with a control group and so forth, and obviously these longitudinal studies can always be open to debate, but the data are quite persuasive. Out of the 1400 patients assessed, there were 825 patients with atrial fibrillation (some paroxysmal, and some permanent) who had a BMI of 27 kg/m2 or more. Obesity is a key issue in patients with atrial fibrillation. Of those patients with a high BMI, 355 agreed to be in the study.

They categorized the groups by weight loss: group 1 lost ≥10%, group 2 lost 3% to 9% of body weight, and group 3 lost less than 3% or gained weight. They also looked at weight fluctuations and whether this had any role in atrial fibrillation. Then they determined the impact of weight loss/weight fluctuation on atrial fibrillation on a severity scale and 7-day ambulatory monitoring.

The results are fascinating. I think the follow-up was for a few years.

Dr Shah: It was 5 years.

Dr Fuster: It is interesting how they tracked the weight loss. Arrhythmia-free survival, both with and without weight-control strategies was greatest in group 1 compared with group 2 and group 3. If you had more than 10% reduction in weight, you had a 45% decrease in atrial-fibrillation recurrence compared with the other groups, which is amazing. If you had weight fluctuation, you didn't really avoid paroxysmal or permanent or persistent atrial fibrillation, so the results are quite substantial. Long-term sustained weight loss, which was accomplished in nearly 70% of these patients, was associated with a significant reduction in the burden of atrial fibrillation. There is so much obesity. Anne you're an electrophysiologist—rather than ablate the atrial fibrillation, maybe we should ablate the stomach.

Dr Curtis: I just want to point out that it really was simple medical weight loss—the patients went to a clinic regularly and they were followed up, but they did not have bariatric surgery. I suppose if you did that, you would get even better results, but I was fascinated by how much of an effect they had without having to do surgery. And one of the big predictors of success was if the patients attended the clinic. If they kept coming back and worked with the program, they lost more weight.

Dr Fuster: You need the system. There was a lot of interaction with the patients. PK, how do you react to the study?

Dr Shah: It's a fantastic observation, and mechanistically very intriguing as to how weight loss affects AF: is it through sleep-apnea reduction, is it through metabolic-syndrome reduction, is it through epicardial-fat reduction that you achieve these results?

Dr Fuster: They quantified all of these results. Blood pressure dropped. Lipids dropped. Glucose dropped. The left ventricular hypertrophy dropped. Left atrial volume dropped. It's unbelievable, all of the parameters that are troublesome went down.

Dr Shah: One of the things that they didn't measure, which we discussed during the presentation, was epicardial fat or pericardial fat, they didn't look at it, but they are going to. There is evidence that inflammation in the fat may create outside N signaling, which could be arrhythmogenic or profibrotic from the atrium.

Dr Fuster: Actually, this is the concept of central obesity, that you have deposition of fat, the macrophages move in to take the fat out and by doing that they release cytokines, which chemically may affect the atrium, this is what you are talking about.

Whatever the mechanism, the risk factors are affected. How do you react to all of this?

Dr Jolly: Weight loss is good.

Dr Douglas: I'm skipping dinner.

Dr Shah: Forty-five percent of these patients at 5 years remained free of any drugs, any cardioversion, and no afib. That is remarkable.

Dr Curtis: When we ablate patients, one of the predictors of lack of success is the fact that they are overweight and they don't lose weight, and you have to factor that in. How do you get a patient to lose weight so they will have the best outcome from an invasive procedure?

Dr Jolly: It probably goes beyond AF, right? Weight loss impacts diabetes. It impacts so many other things.

Dr Moat: With that degree of weight loss, you would expect the sugar to come down and the blood pressure, but the striking thing to me is that they saw changes in left atrial volume and left ventricular and diastolic dimensions that were incredible.

TOTAL: Routine Aspiration Thrombectomy vs Primary PCI Alone in STEMI

Dr Fuster: After all this excitement, now we go to the boring topic of intervention. We have a couple of papers that are worth mentioning, because the data that preceded these papers were confusing. Let's talk about thrombectomy first.

This is the TOTAL study,[14,15] a randomized trial of primary PCI with or without routine manual thrombectomy, and Dr Jolly was the principal investigator of this international study of about 10,000 patients with ST-segment-elevation myocardial infarction [STEMI], who underwent primary PCI with a strategy of routine up-front manual thrombectomy vs PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association class 4 heart failure within 180 days. The safety outcome was stroke within 30 days.

The primary outcome was 6.9% in the thrombectomy group vs 7% in the PCI-alone group, so no difference at all. In terms of stroke within 30 days, it occurred in 0.7% of the thrombectomy group vs 0.3% in the PCI-alone group, so it was somewhat increased. By the way, this is the largest study ever done on thrombectomy in patients with STEMI, and it concluded that routine manual thrombectomy as compared with PCI alone did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association class 4 heart failure within 180 days but was associated with an increased rate of stroke within 30 days. Are you surprised?

Dr Jolly: Yes. We had hypothesized that it would be beneficial. As interventionalists we love sucking clot out of the coronary artery. It makes us feel good. It makes the angiogram look better.

Dr Fuster: Will you stop tomorrow?

Dr Jolly: Yes. It is important to stop. We have an ocular stenotic reflex to not only do angioplasty but also to use certain tools, and it made us feel so good to suck the thrombus out, put it in a little bowl, and everybody celebrates with a high five, but clearly this is not the right approach.

Dr Fuster: Could the results be due to a technical issue?

Dr Jolly: It is a good question. When we looked at site-by-site interaction, we did not see that this effect on stroke was dramatically more at some sites vs others. The other interesting thing related to volume. High-volume PCI operators should be better, yet their stroke rate was the same as the low-volume guys who don't do very much, but, that being said, we cannot rule it out. It was a large study, 10,000 patients, 20 countries, so even at a single center there are certain operators who are very good and certain operators you don't want your mother to go to. That is the reality.

Dr Fuster: Pamela, how do you react?

Dr Douglas: I think less is more. This is one of those studies where we find out that something we thought was good and added to the procedure probably doesn't, and we need to do less.

Dr Fuster: What do you think, Neil?

Dr Moat: It is an excellent study, and it shows there is no role for thrombectomy.

Dr Fuster: You surgeons don't think in these terms, you operate anyway.

Dr Moat: Well, we certainly don't like operating when there is thrombus in the vessel.

Dr Fuster: Anne, how do you react to this?

Dr Curtis: I agree with Pam that less is more, and it also means that you use a few less tools when you are doing the procedure, and the cost should be lower for an equivalent outcome, so why not?

Dr Fuster: The whole concept of thrombectomy is that you decrease the degree of emboli distally, and we have data suggesting that ST resolution is faster with the use of thrombectomy, but in TOTAL, when they looked at the distal emboli and ST-segment resolution, even those the results didn't go in the right direction. Why do you think this is the case? It's a little bit paradoxical.

Dr Jolly: What is interesting is in the brain, thrombus removal has had multiple New England Journal of Medicine articles showing it lowers mortality, it improves functional outcome, and so we were hoping we would find a similar outcome in the heart. Clearly we didn't, and it may be that the heart is a much more resilient organ than the brain.

Dr Fuster: PK, any comments?

Dr Shah: I was thoroughly disappointed that something that intuitively made sense and was supported by some of the prior studies didn't pan out. I still don't understand why it didn't, and the stroke-risk increase is also a little bit strange. Is it manipulation of the thrombectomy catheter that is likely to trigger stroke by damaging the aortic arch? What is the explanation for increased stroke risk when you are working on a coronary?

Dr Jolly: Sometimes we are pulling out long strings of clot, and you can lose some of that. You can lose it either in the coronary system, or you can lose it out the aorta, and it can go elsewhere, so that is a potential mechanism. The other potential mechanism is guide catheter manipulation to get this device down, and interventionalists don't hesitate to backwall the guide, but that is scraping the aorta, and that can be a cause.

Dr Douglas: But that should impact all-cause procedural stroke, not 30-day stroke, much less long term.

Dr Fuster: Was it difficult to do the study; in other words, were the interventionalists easy to randomize?

Dr Jolly: The hardest thing was that interventionalists believed in it so much that we had to do a lot of convincing for them not to use the device. The most common reason that a center would refuse is that thrombectomy is like antibiotics for pneumonia, I know this works, and so I can't randomize.

Dr Fuster: You were disappointed?

Dr Jolly: I was, of course.

Dr Fuster: It was a good study, and it is the largest one. Do you think it is definitive?

Dr Jolly: Well, you never can say, but we think so.

MATRIX: Transradial Vs Transfemoral Access In Patients With ACS

Dr Fuster: Well, you are not the PI for this next study on radial vs femoral access.[16,17]

Dr Jolly: I wrote the Lancet editorial[18] for this trial.

Dr Fuster: Too many big shots on the panel today. There are two different parts of the MATRIX study: the access-site program, and the antithrombotic program. We'll discuss both, but let's start with radial vs femoral access in patients with acute coronary syndromes undergoing invasive management, a randomized, multicenter trial. The first author of the paper,which was just published in the Lancet, is Dr Marco Valgimigli, who also presented the data.

In this study, 8000 patients with STEMI or NSTEMI were randomized to radial vs femoral access for coronary angiography and percutaneous coronary intervention. It was a 30-day study, and the primary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and then there are the net adverse clinical events, which included bleeding. The primary end point occurred in 8.8% of patients with radial access vs 10.3% in the femoral-access group. These did not reach statistical significance, but it was significant when they looked at the net adverse clinical events (with bleeding), which occurred in 11.7% in the femoral-access group and 9.8% in the radial-access group.

I don't know if it is surprising that the benefit had a lot to do with the bleeding aspect, but all-cause mortality was also reduced, and maybe both are linked. The authors concluded that in patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events through a reduction in major bleeding and all-cause mortality. Sanjit, you wrote the editorial on this paper—can you give us a take-home message?

Dr Jolly: I think the message is the future of coronary angiography is going to be through the wrist. It certainly decreases bleeding, and that makes sense because the femoral artery is a big vessel and there is the retroperitoneal space behind it and it is harder to compress. Patients prefer transradial. Now, the question is, is the mortality reduction real, and is it related to the difference in access site? We don't know the ultimate answer. It was a nominal but significant P value. From a patient perspective, if I can have a procedure through my wrist and then go home in an hour and a half or have a procedure through my groin with a slightly higher risk of bleeding and be in bed for a number of hours, I think most people would choose the wrist.

Dr Fuster: What about the individuals who have been trained all of their lives doing femoral? If you are comfortable with one technique, it will be difficult to change.

Dr Jolly: You are right, but why shouldn't it be like any surgical technique? For example, when laparoscopic surgery came around, the older surgeons learned the laparoscopic technique. With radial vs femoral, once you get in the coronaries, everything is the same, so it will take a year to buddy up and learn, but it is not that dramatic.

Dr Fuster: This was coming based on the previous studies.

Dr Jolly: Yes, in fact, if you looked at the TOTAL study, 70% of procedures were done through the wrist.

Dr Fuster: Pamela, do you have any comments?

Dr Douglas: I would just comment that there are particular patient subgroups where we should be thinking about with this, those at bleeding risk of course, which is often women because of body size and dosing issues; the elderly again, also women; the obese, in whom hemostasis is harder to achieve through femoral access. If people are reluctant to go whole hog and do 100% transradial, at least do a risk-based radial and try to lower the risk in some of those higher-risk groups.

Dr Jolly: However, I would argue that those are the toughest patients to do transradially, so you have to be good to do those subgroups successfully. One of the important messages from MATRIX and from a prior study I did, the RIVAL[19] study (with 7000 patients) is that there is a significant interaction by operator volume, so the benefit is primarily in those operators who are good.

Dr Fuster: Anne, as an electrophysiologist, in terms of access, does this study tell you anything?

Dr Curtis: The results are impressive. In taking care of these patients in the coronary care unit, the mobility that you get for the patient immediately afterward is very good. I don't know that it helps us much in the electrophysiology world, because our procedures are so much on the femoral venous and transseptal side, but I think it is an impressive result and even the old-timers have learned how to do radials, and more and more catheterization procedures are done transradially.

Dr Fuster: Neil, as a surgeon?

Dr Moat: I think the radial is the way forward. In the femoral arm in MATRIX, the punctures were not ultrasound guided, correct?

Dr Jolly: That's right.

Dr Moat: There are two very large trials[20,21] showing that you can significantly reduce femoral complications by ultrasound guidance, but that does not seem to have been incorporated into clinical practice, certainly not in the UK. So there are other things that you can do to improve femoral-access complications, which don't seem to have gone into clinical practice.

Dr Fuster: PK, it's not a problem for you because you do CT angiography?

Dr Shah: Correct, and for coronary intervention or coronary diagnostics, clearly radial is becoming the preferred route. Obviously for structural heart disease intervention, it is not an option yet.

MATRIX: Bivalirudin vs UFH in Patients With ACS

Dr Fuster: From the same MATRIX group we got the antithrombin program on the use of heparin vs bivalirudin, and the results were equal, there was no difference. I don't know how to interpret that, because as you look further into the data, everything was trending against heparin: thrombotic events, cardiovascular events, hemorrhage, and then you end up finding that this is exactly the same in both groups. Sanjit, can you explain this? The story of bivalirudin and heparin is quite tricky. It has been back and forth.

Dr Jolly: For a long time people believed that bivalirudin was better in terms of lowering bleeding, but the Achilles' heel is that it may be not quite as effective in terms of antithrombotic and you get more stent thrombosis, so there was this balance between bleeding and thrombosis. The other issue of course is cost. Heparin is pennies vs hundreds of dollars for bivalirudin, so many people around the world were saying "I use radial access, I use low-dose heparin, I don't need to spend hundreds of dollars on bivalirudin." And there was a UK study (HEAT-PPCI) that suggested that in fact you get a lot more stent thrombosis and maybe more MI with bivalirudin.[22] The MATRIX study is very interesting because the MI rate was quite high, but it was not different between the two groups. The authors seemed to argue that it was a neutral study because the MI was so high.

Dr Fuster: It diluted the data.

Dr Jolly: It overshadowed the benefit that they saw in terms of bleeding and mortality.

Dr Shah: I remember at the ACC last year there was a lot of heated debate on the subject between the European group and the US group.

PARTNER 1: Transcatheter vs Surgical Aortic-Valve Replacement 5-Year Data

Dr Fuster: I would like to finish with a word on the PARTNER 1[23] study on transcatheter aortic-valve replacement vs surgery in the high-risk population, and at 5 years of follow-up they do very well, the patients who underwent the percutaneous procedure. Do you have any comments, Neil?

Dr Moat: It was a very interesting late-breaking trial session on TAVR, the PARTNER trial 5-year data and 2-year results of the CoreValve.[24]

Dr Fuster: It looks good.

Dr Moat: TAVR looks very good. One word of caution is that the surgeons had their arms tied behind their backs a little bit in these trials, in that they weren't allowed to implant stentless valves in small roots, and they weren't allowed to do root enlargement, so almost 50% of the patients in both the PARTNER and CoreValve trials had stented bioprosthesis size 19 mm and 21 mm, resulting in a lot of patient-prosthesis mismatch. A word of caution about whether the surgery done in the surgical arm really represented real-world surgery.

Dr Fuster: Pamela, a comment?

Dr Douglas: In PARTNER 1 they didn't have the larger size of the Sapien transcatheter-valve either, they just had the two sizes. Just in disclosure, I am part of the core lab and an author on that paper. This is the first time we have had 5-year core-lab hemodynamic results in surgical aortic valves because there had never been a large, randomized controlled trial of a surgical implant, so the data are really important.

The gradients went down and stayed down. Valve area went up and stayed up for both devices, so a very nice hemodynamic result.

Dr Fuster: Anne?

Dr Curtis: Having the longer-term follow-up is so critical because we knew for a while now that short term, everything was okay, but if you were going to wind up with patients at 5 years being right back where they started from, it wouldn't have been much of an advance, so I think this is very important.

Dr Fuster: PK?

Dr Shah: It is the way of the future for aortic-valve replacement for most patients.

Dr Fuster: But I am still worried.

Dr Shah: Right, well, we don't have very long-term data. We have intermediate-term data.

Dr Fuster: I am worried about the head.

Dr Shah: In the recent iteration of the Sapien 3 valve the risk of stroke was very low.

Dr Fuster: I am talking about silent stroke. If you do MRI, 70% have new lesions, and there is no good analysis of cognitive function being done. In the future, this may be used in younger and younger people. I am cautious until we learn what happens with the cognitive function. That is my point.

Dr Shah: And longer-term 10- to 15-year follow-up, I think.

Dr Moat: Going back to what Pamela said, I think you are completely right to highlight the long-term core-lab follow-up for surgery. There are some big lessons for surgeons from those two trials, in that surgeons may need to up their game a little bit to put bigger valves in.

Dr Douglas: The other thing to note is that the paravalvular-leak/mortality signal was preserved. That is important. With these valves we not only need to learn how to craft the device itself but also how to implant them in such a way that you don't rupture the root in the annulus when you are implanting them, but you inflate these balloon-inflatable valves enough.

Dr Fuster: It is promising. Thank you.

BEST: EES vs CABG in Multivessel CAD

Dr Fuster: Moving along. When we presented the FREEDOM trial[25], everybody said the second generation of drug-eluting stents are going to wipe out surgery. Well here comes the BEST trial[26,27] on everolimus-eluting stents vs bypass surgery in multivessel coronary artery disease. You actually don't need to be diabetic to be in this trial. The bypass patients did better. What is your opinion, Neil?

Dr Moat: It is obvious that surgery is better.

Dr Fuster: What do you think, Sanjit?

Dr Jolly: Number one, it's an underpowered trial, and the real finding for me is death and MI. I think we need a bigger trial. That being said, repeat revascularization is not such a big deal, but what I want to know is if the mortality is different. The existing data absolutely support bypass surgery in patients with multivessel disease, particularly complex multivessel disease, so I think the only patients where there is some equipoise is patients with very low SYNTAX score.

Dr Fuster: Bob Harrington wrote the editorial.[28] It was underpowered. They stopped the trial.

Dr Shah: And the softest end point is repeat revascularization.

Dr Fuster: Anyway, at least it doesn't go against our surgical friend's opinion.

Dr Moat: It also goes in the same direction of other bigger studies like SYNTAX.[29]

AATAC: Ablation vs Amiodarone for Persistent AF in Patients With CHF and ICD/CRT-D

Dr Fuster: The final trial that is really in your court, Anne, has to do with patients with atrial fibrillation. This is the AATAC study in 200 patients with atrial fibrillation comparing ablation vs amiodarone. These patients were in cardiac failure, and at follow-up, 70% of the patients with ablation were still in sinus rhythm vs only 30% of the amiodarone patients, and 10% of the amiodarone group had to discontinue the drug because of side effects. I don't think this is surprising. Do you?

Dr Curtis: No, we have had other studies before showing that not only does ablation trump drugs, but also that ejection fraction gets better in patients who have systolic heart failure and atrial fibrillation. You can show that you do better from a functional standpoint as well as in terms of being arrhythmia-free. We still don't know about survival. That is the one thing that has been hard to demonstrate, because the trials aren't large enough or long enough to show that.

Dr Fuster: This is great, wonderful. Thank you very much for being here with us. It was a good conversation, and I hope we can discuss other issues again. I think that this meeting provided some material for us to digest. Thank you all very much.

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