Top Cardiology Trials of 2021

; C. Michael Gibson, MD


December 16, 2021

This transcript has been edited for clarity.

Robert A. Harrington, MD: Hi. This is Bob Harrington from Stanford University. It's become an annual end-of-the-year tradition the past several years that my good friend and colleague, Mike Gibson, and I do a roundup of what we've learned over the course of the past year in cardiovascular medicine, particularly from the trials. We're going to go rapid-fire through a number of topics. I'd like to cover ACS, CAD, heart failure, chronic kidney disease, and interventional surgery.

Sometimes we take a deep dive into data, but this time we're going to try to hit at a higher level and give you our views or concepts, if you will, that we think are driving these fields.

Fortunately, our colleagues at Medscape are going to link all of the trials that we talk about so you can get the actual data to do a deeper dive yourself. Mike and I will try to reflect and give you our opinion on how we see things in cardiovascular medicine as having shaped up in 2021.

With that, let me introduce my good friend and colleague, Dr Mike Gibson. Mike is an interventional cardiologist at the Beth Israel Deaconess in Boston. He's a professor of medicine at the Harvard Medical School and he is the director of the Baim Institute and academic research organization. Mike, as always, thanks for joining us in this end-of-the-year show on Medscape Cardiology and

C. Michael Gibson, MD: Great to be back with you, Bob. I do think people really want context and they like it when we digest things and put things into context rather than the deep dive on details. I look forward to our new format this year.

Remote Trials

Harrington: Mike, the first thing that I'll get you to comment on...Wow, when I started preparing, and then when you and I were going back and forth over email the past couple of days, there was an amazing amount of new information that came out this year, despite the fact that none of us have, for the most part, been anywhere since 2019.

Gibson: Well, I was surprised because you and I both know there are many big trials out there that have really been slowed down due to COVID. I was dumbfounded by how much information, how much data, and how successful people were in completing high-quality studies during the COVID era.

Harrington: Yeah, I think that's a whole lesson to take away, isn't it, from the COVID era. Remote data monitoring, remote visits, sending people home with devices so that you can collect material, sending physiologic material, sending people out to a subject's home to get blood tests and EKGs. Pretty remarkable, isn't it?

Gibson: I hope it changes things. I hope we take some lessons to heart. I hope regulators realize that we can do a good job with remote monitoring and telehealth visits. Obviously, can't get an EKG or blood. But for so much of what we did — having people drive in, pay $40 to park, take time off to bring their relative in — I hope we can pivot away from that and do things simpler and more efficiently. I hope this affects the cardiovascular trial world in a positive way.

Harrington: One of the things you and I will talk about today is that some of the questions that have been addressed are awesome questions and really important clinically, but maybe the trials were underpowered. Other trials in cardiovascular medicine are sufficiently powered to even detect relatively small differences. I'd like to see more of the latter and less of the former. Maybe if we can focus on what's really important, we can get big trials done to answer some of these clinically relevant questions.

Gibson: You and I lived through the mega-trial world. Now I call it the giga-trial world. When you have hundreds of thousands of patients enrolled in China in cluster designs, you are much more likely to get a definitive answer to the question. As you say, Bob, we always in the back of our head have to say, "What's the P value here?" The P value is statistically significant, but the P value for the patient — is it clinically meaningful? The P value for the payer — is it cost-effective? It's a different approach. We'll answer the question definitively. We just have to put it into clinical context.

Dual Antiplatelet Therapy

Harrington: Perfect segue to the first grouping that I want to dive into, the area that you and I have spent a lot of time in the past 30 years, and that's acute coronary syndromes, coronary artery disease, and interventional cardiology, particularly percutaneous coronary intervention (PCI). We've been using dual antiplatelet therapy (DAPT) for a long time now, and we've been using many different agents. There have been head-to-head comparisons. Boy, this past year has told me that there are still many questions left.

Also, we've learned some new things. I'll just throw a couple things out there and get you to riff on them. First off, we've always been talking about prolonged DAPT, and we had a trial of prolonged DAPT. It really is looking in new stance with other therapies that shorter and shorter durations of DAPT are possible, particularly in high-bleeding-risk patients, which is something that our friend Roxana Mehran has been particularly interested in studying.

Second, Mike, is this notion of going from DAPT to single antiplatelet therapy. Oh, and guess what? That single antiplatelet therapy might not be aspirin. Third, de-escalation. This is something I've always sort of talked against because the studies did x with clopidogrel. The studies did y with ticagrelor. Why would you switch back and forth? Well, now maybe we have some data around de-escalation.

Finally, a trial that we were involved with aspirin. You were involved with the aspirin trial. How did we not know the right dose of aspirin? After ADAPTABLE, do we still not know the right dose of aspirin? Tell us what you think about what happened in this world over the past year.

Gibson: Well, the message is that the world has changed. When you and I were young interventional cardiologists, we had bare metal stents and we were putting people on dextrin, Coumadin, Ticlid, or Persantine. They were just waiting to bleed, and in fact, they did bleed and then that bleeding was the biggest risk factor for stent thrombosis. We hadn't figured it out yet. I think ticlopidine really did revolutionize the world when we switched over to DAPT.

Obviously, some better drugs came along after that. But what's fascinating is that we thought we needed a year. That was the intuition that, after an ACS event, you would need a year. Obviously, then, people began to say more than a year was needed. We had PEGASUS and the DAPT study to see if we needed to extend beyond it.

I think the world has changed dramatically since those days. Now we have thinner stents. We have better biopolymers that are less inflammatory. We have much more aggressive lipid lowering. We live in a world now of high-dose atorvastatin with combinations with things like ezetimibe. We have a fair amount of use, which is growing, of PCSK9 inhibitors. We have many other strategies, such as more aggressive blood pressure lowering, ACE inhibitors, and everything else. People are getting treated with much more evidence-based medicine and event rates have really dropped.

As we're planning contemporary trials, we're starting to see that there aren't as many events out there as there used to be, and there aren't as many STEMIs. We always focused on efficacy. We always focused on number needed to treat and number needed to harm. You know what I always say, Bob: It's also NNB, or number needed to blame. Interventional cardiologists don't want to get blamed for bleeding events. We do know that bleeding is associated with frailty. I'm not sure it's quite as dangerous in terms of a multivariate predictor of outcomes, but it may lead people to stop their drugs.

This, of course, led to the effort that we're talking about to shorten and shorten and shorten the duration of antiplatelet therapy or DAPT. We're now talking in some scenarios, particularly if someone's on an anticoagulant, to stopping at hospitalization. Less may be more.

Here's my concern, Bob. I think we may have been cutting corners a bit on some of the early studies. They were awfully small. They showed noninferiority. I get nervous about small noninferiority studies saying that it looks like it's okay to shorten things. They had very broad confidence intervals. I am thrilled that we had two recent studies like MASTER DAPT that was pretty big, with thousands of patients. People have concluded, "Well, there you go. You can shorten DAPT significantly without a penalty in terms of efficacy."

I want to highlight one limitation in that these people had made it a month after their event, after their PCI, without having an ischemic event. It was cultivated for lower-risk ischemic patients, and it makes me a little concerned about the conclusions we draw.

Then there was a study that showed the opposite, STOPDAPT-2, where it didn't look like it was necessarily safe to stop early in a fairly well-powered study. There are some different answers, but much of it is driven by the ischemic and bleeding risk of the patient.

Finally, Bob, what's the right drug for chronic therapy? We had the HOST-EXAM study that showed, again 25 years after CAPRIE, that clopidogrel bested aspirin. It's a question that needs to be readdressed in the modern era. Some of us are putting together a big PCORI grant to try to answer that. As many questions as there are answers — maybe more questions — the world is changing.

Harrington: I love the way you summarize it, Mike. I also like this notion of the individual risk. One of the lessons that I learned from Bobby Yeh's paper on the DAPT trial was that many of the events that occur in the stented patient are not due to the stented segment.

Gibson: 54%.

Harrington: They're having events elsewhere. That group got benefit from the dual strategy. I think you're right. I think we're going to move to an era with more and more data that we're going to be able to do better risk prediction and really get to what we all want to get to, which is what's the right combination of drugs for the right patient at the right time?

Gibson: The right time, and that's one of the big issues with risk prediction. You make a risk prediction at baseline, but if someone hasn't bled after 3 months, they're a different patient. They've declared that they tolerate the drug. I think we need an iterative approach to risk assessment. You wouldn't try to predict the weather a year from now. You would look sequentially to modify your risk. I think we need to do more in terms of risk modification.

Finally, Bob, I hate to say it. We're interventional cardiologists, but you know what, there's a patient attached to the stent. I don't want to see us lose the focus on secondary prevention, which I think we're a little bit at risk for here with just this focus on treating the stent.

Another Good Year for SGLT2 Inhibitors

Harrington: Yeah, I completely agree with that. As you know, I joke that I'm now a reformed interventionalist. I've moved my practice to general cardiology, and it does force you to think of it differently when you're seeing patients week after week in the clinic. It's been a good thing in my career over the course of the past few years.

I'm going to transition us now. Heart failure that I'm going to combine with CKD. I think you know where I'm going. CKD has certainly emerged over this past year. It's always been important, but boy have we learned a lot about CKD the past year.

The topic last year was SGLT2 inhibitors. I think the topic this year is SGLT2 inhibitors. Yes, there are some other drugs from FIGARO and FIDELIO with other agents, but let's have this conversation around SGLT2 inhibitors. Boy, some real success. We still have things to learn, but certainly, now, I think it's safe to say it's cornerstone therapy for heart failure.

Gibson: Absolutely. By the way, it's tough to be the fourth or fifth kid on the block and show benefits on top of all those other drugs. Imagine if those other drugs had to show benefits on top of this class. As Dr Braunwald, my mentor and close friend, said, this class of drugs is the new statin.

I go to many meetings these days with people in the renal area. Unlike cardiology, they're often very pessimistic. They haven't had a win for their patients in a long time. When you ask them what works for their patients, they say nothing works. This is so great to see something that actually may improve people for that axis, particularly where you have heart failure and kidney disease or heart failure with diabetic kidney disease . This is a big win for patients.

Harrington: Yeah. I like the way you say it, Mike. We've talked about CKD being a CAD risk factor. It certainly is at this nexus, as you've said, of coronary disease, metabolic disease, and heart failure. It's all intertwined. I actually have applauded my heart failure colleagues coming out of HFSA this year. There was talk about forgetting about HFpEF or HFrEF; if they have clinical heart failure, here are the foundational drugs people need to be on. I know that's a little bit of an oversimplification. There are certainly things we can learn about understanding the pathophysiology, but it's not a bad strategy to say that if your patient has signs/symptoms of clinical heart failure, these are the classes of drugs they ought to be on.

Gibson: Bob, we have all grown up targeting one arrow with drugs. There are so many arrows affecting the kidney and itself in the heart and its function. I think what we're starting to zero in on is something that you and I probably both intuitively knew: Low starting doses of multiple drugs affecting multiple pathways might be the right starting point. Then, looking at some of the different parameters and escalating those. I was really scared of the idea of starting four or five drugs at once in a heart failure patient, but I circled around to philosophically and pathophysiologically, that's probably the right strategy. Let's hit all the arrows and then escalate as appropriate.

Harrington: Yeah. What it also brings in for me, Mike, is that you need to have a team help you do that. You have to have close follow-up with the patients, people have to call the patients, and people have to be on the patient portals with the patient. To your point, if I'm going to start you on three, four, or five new drugs, I've got to take some responsibility for my team being able to help you manage that.

Semaglutide for Weight Loss

Gibson: Bob, can I throw in a good word for another class, the GLP-1 drugs? Personally, I think this class of drugs could totally revolutionize coronary artery disease. We're talking about, with a year of therapy with this drug, people losing 5 inches off their waist and losing on average 30-40 pounds, bringing their BMI down significantly. I think we have to be honest that a large proportion of heart disease is a disease of lifestyle. We have a diabesity epidemic. In the future, moving forward, I think this is going to be a critical class of drugs not just for primary prevention, but maybe even moving into primordial prevention, to really prevent the epidemic that we have.

Harrington: Yeah, we have seen some trials this past year with the injectable GLP inhibitors that have been extraordinary. The amount of weight loss, as you said, is not what we had come to expect in medical obesity management, the 5% body weight. We're talking big shifts of weight, and with better control of diabetes, better lipid control, and better blood pressure control. Mike, I agree with you, and I think the data are pretty compelling. We're going to need longer outcome data, etc. I don't think any of us would shy away from that, but I'm with you. This is an important class of drugs. Thanks for bringing it up.

Cardiac Surgery Trials

Let's shift gears again, Mike, into an area where you and I have spent much of our professional life: interventional cardiology and cardiac surgery. One of the things for me this past year is that I've loved every big meeting, seeing at least one or two trials from our surgical colleagues, asking really important questions about the technical stuff that they do. Let's talk quickly about LAAOS III, the left atrial appendage occlusion trial. Wow, that that was a clever design — well designed, well powered. Do you want to talk about that for a minute?

Gibson: Yeah. Closing off that left atrial appendage at the time of surgery reduced the risk for embolic events by one third, as I recall. I think it is important. I think it probably should change practice, but then it brings up the question of left atrial appendage closure percutaneously. I don't think the results can be translated one-to-one to the percutaneous approach by any means. It certainly, philosophically and pathophysiologically, indicates that there's something there in terms of preventing embolic events.

I think we still have some limitations with where we're at with those devices. There is still a risk for device-related thrombosis, clot forming on the devices, in about 3%. There are variable rates of leak around the device, where in maybe 5% or 10% there's a leak where clot could go out. There's much evolution in this class of devices rapidly. I hope our device colleagues will embrace the idea of combining some of these devices, which are prothrombotic and have surface activation of the clotting system, with some of our newer drugs.

Particularly, Bob, I'm thinking about the Factor XI inhibitors, which do a great job at contact activation. Precisely this scenario, where you activate the clotting system with contact with a device like this. I'm hopeful that we see a marriage. I'm pushing the manufacturers to marry some of the very good devices for some of the newer drugs coming along. I hope we can make some advances there.

Harrington: Yeah, this will be a topic you and I can riff on next year because you and I are both involved with Factor XI inhibitor trials, and I think that is a promising class of anticoagulants. Maybe we can give people an update next year, Mike, when we get together.

Another great trial that the surgeons conquered or attempted was focused on what to do when you're repairing the mitral valve when you have concomitant TR. That's an important clinical question, right? Do you do assume that as you lower left atrial pressures and lower pulmonary artery pressures, that that's going to translate ultimately into less TR? What do you say, structurally, when that valve has been damaged and we're going to have to cinch it up a bit and put in a ring, etc.? They did a randomized comparison. What do you think of that one?

Gibson: Again, I applaud our surgical colleagues for the rigor with which they're doing these things. By the way, Bob, yesterday, a statement came out in Circulation from the AHA on surgical trials and the methodology to do these trials. There have been tremendous advances, but you're right, Bob. Once the horse is out of the barn, you may need to do more than just fix the one valve.


Harrington: Yeah, and I, again, applaud my surgical colleagues, this one done through the CT surgical network through the NHLBI. Just the fact that they're willing to tackle some important questions like this. I saw the Circulation paper as well. It's a really important statement and kudos to our surgical and medical colleagues who are working together in that network.

FAME 3. My colleague here, chief of cardiology at the Palo Alto VA, Bill Fearon, really worked hard on this one, trying to understand whether, if you really do complete revascularization using FFR guiding vs bypass surgery, what will the outcomes be? Well, the surgeons won on this one, didn't they, with CABG with advanced disease.

Gibson: I love Bill. I think he's set a high bar for himself. To beat surgery in complex disease, I don't know that we're there. I think surgery still wins. I don't know that that's necessarily a bad rap on the technology for the less severe lesions. Sadly, I think some people took away the message that FFR is not helpful. I don't believe that. I do think that in a less severe range, it is very helpful.

I think there's been a tremendous advance that I'm very excited about, which is the computerized assessment of FFR based on angiographic images. Bob, for 35 years now, I've run an angiographic core lab and we've been analyzing arteries and their volume in multiple dimensions. Of course, I invented the frame count, and we know how long a time it took up to fill that volume. Knowing volume and time, we have flow.

Knowing flow and knowing the geometry, now there's really great computer fluid dynamic modeling software that looks at resistance and does FFR in the lab from the angiogram. What we're seeing are a series of studies showing that, like the pressure wire, it can tell you that you don't need to intervene on this lesion. I always see it in the LAD. It may not look that tight, but it's a longer lesion and you really should intervene on that one. It's inexpensive. You won't have to put a wire in, no complications, no thrombotic complications, and no dissections. I think it could really change cath lab management. Don't give up on FFR.

Harrington: No, I'm not giving up on it at all. I think that Bill has done us a real service of being able to think through the issues associated with when you use FFR when it provides the most incremental information.

Like you, I liked the secondary analysis of FAME 3, where they showed that there really is a gradation of benefit of surgery over percutaneous revascularization based on the SYNTAX score. Again, it gets to our earlier conversation, Mike, of trying to find the right approach for the right patient at the right time. Using our tools that we have available — in this case, physiologic flow — can be an important way to help clinicians and patients have informed decision-making.

Gibson: Absolutely, but you know me. There's so much going on beyond the stenosis down in the microvasculature. Bill and his team, and you guys at Stanford, are doing a great job looking at looking at the index of microvascular resistance (IMR). That offers the hope, also, of really risk-stratifying.

Also, during a STEMI, the IMR is now being used to say, "Do I need to give something down into microvasculature? One for the road for a lytic or a glycoprotein IIb/IIIa inhibitor or vasodilator, or am I good to go? It's starting to creep into trials, and it someday may be part of our decision-making armamentarium.

Harrington: Well, there's a whole other conversation we could have about the adjunctive medical therapy to, for example, primary PCI. It's more than just getting in there, opening it up, and leaving. There may be groups of patients; certainly, the shock patient is at the extreme. As you point out, there are gradations of abnormal microvascular flow. You've shown this with myocardial blush, that we really need to think about what should be the additional therapeutic approach.

Gibson: I have to emphasize that, again, the LAD and the right coronary artery are two different animals. The LAD beads a thick-walled ventricle, it's longer, there's a greater amount of myocardium at risk, and you get large amounts of edema in that LAD territory. It behaves totally differently from our right, which is a larger, wider vessel, more clot, shorter, and feeds into a low-pressure system, so we will probably need very different strategies of how to manage all this.

Harrington: Well, Mike, over the past almost half-hour we have covered an amazing number of topics, and I still have another dozen that I'd love to chat with you about. I know that you and I have gone back and forth through all the trials. This has been a fantastic conversation. I hope people enjoy it. Mike, I hope you're going to stick around when you and I do our second segment at the end of the year, getting into some of the big public health issues, including the trials in the COVID population.

Thanks to our listeners for joining in. Thanks to my good friend, Mike Gibson, from Boston, for having this conversation with me. Do join us for part two of what went on in cardiology in 2021. Thanks, Mike.

Gibson: Thanks, Bob. I think we need a semiannual review.

Robert A. Harrington, MD, is chair of medicine at Stanford University and former president of the American Heart Association. (The opinions expressed here are his and not those of the American Heart Association.) He cares deeply about the generation of evidence to guide clinical practice. He's also an over-the-top Boston Red Sox fan.

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