Recorded December 7, 2023. This transcript has been edited for clarity.
Robert A. Harrington, MD: Hi. This is Bob Harrington from Weill Cornell Medicine on theheart.org | Medscape Cardiology. Today we are taping my favorite podcast of the year, the wrap-up that I've done for a number of years now with my good friend and colleague, Mike Gibson. We get to talk about some of the hot news in cardiology that played out over the course of the year. We tend to go through the trials and then maybe hit some big topics on either the news of cardiology or the policy issues affecting cardiology. And along the way, Mike and I might add a few other topics.
Typically what we've done is to group topics like heart failure, intervention, and lipids. This year we're going to walk through the calendar year, and we'll start with ACC '23, work our way to ESC '23, and end up at AHA '23. So with that as the plan, I'm really pleased to be joined by Mike Gibson. Mike is an interventional cardiologist at the Beth Israel Deaconess Lahey Hospital in Boston. He's a professor of medicine at Harvard Medical School, and he is the CEO of the BAIM Institute for Clinical Research, an academic research organization. Mike, thanks for joining us on Medscape Cardiology.
C. Michael Gibson, MD: Always my favorite podcast of the year.
Harrington: Oftentimes you tell me, "If you really want people to listen to it, keep it less than 5 minutes." But in this particular case, you and I like to really riff on these topics.
Gibson: Sounds great.
Bempedoic Acid and Statin Intolerance
Harrington: So ACC '23 returned to one of my favorite cities for a medical meeting: New Orleans, Louisiana. Always a great time. You certainly get your steps in at that convention center. You also have great food, great areas for networking. All in all, are you a fan of New Orleans for the meetings?
Gibson: I love New Orleans. it's a city where you get to literally bump into everyone you know; it's not too big. Probably one of my favorite cities.
Harrington: When I go to New Orleans, I get a taxi or Uber on the way from the airport to my hotel, and then back to the airport. Most of the rest of the time, I'm walking.
ACC '23 was a terrific meeting. And I've picked out a couple of things I want to talk about, both in the lipid space, because I thought they were important for different reasons. The first one was CLEAR Outcomes. This trial was done in statin-intolerant patients, an important group of patients that we all see. We can talk about how they chose to find the statin-intolerant population. They were randomized to bempedoic acid, which is a new LDL-C–lowering agent, and some terrific results from this trial showed that the addition of bempedoic acid to other therapies led to a meaningful reduction in clinical events.
Mike, give us your overall impressions of the trial, but I don't want you to talk about the statin-intolerant population.
Gibson: Whether you want to admit it or not, at least patients perceive that they are intolerant to statins. There are some data to suggest it may not be real; but in the patient's mind, it's very real. So we need alternatives to statins.
They had to either not be able to take two statins in the past or not be able to take one statin and unwilling to try a second one; that's how they got into the study. This drug is metabolized in the liver, a bit above where a regular statin is metabolized. It's not metabolized in the periphery or in the muscle, so you don't have that potential for muscle pain. And as you said, they had good outcomes: 13% relative risk reduction in death, myocardial infarction (MI), stroke, revascularization, and about a 1.6% absolute risk reduction — that's pretty good. And then on the triple endpoint, a 15% reduction in death, MI, and stroke. For my thinking, this is good news because it's always good news to have alternatives, and this is a well-tolerated alternative for patients with statin intolerance.
Harrington: I really liked the way they did the design because the criticism is always, "Oh, did you really find people who were statin intolerant? And did you do a muscle test? Did you have elevations of creatine kinase, etc.?" But they just wanted documentation that this patient has not been able to tolerate statin, so in many ways it was real life. That's what we're all faced with. You can say, hey, there's no objective measure here. And you can say, hey, there have been trials with the nocebo effect, and yet what they did was very practical; they said, you know, these are patients who just haven't been able to take a statin.
Gibson: Yep. There's another nonstatin therapy, ezetimibe, with about a 10% relative risk reduction; here you're getting about a 15% risk reduction. So I think it stands up pretty well.
Harrington: You start to picture that patient whose LDL-C is really high. You get them on a statin, it lowers it by a predictable amount, but they're still higher than guidelines, whether it's primary secondary prevention; you add ezetimibe, as you said, and you get your 10% reduction, very safely done. Maybe now you add bempedoic acid.
It's always good to have choices, particularly in this field. We're really trying to drive LDL-C lower and lower.
Along the same line, another important trial — a phase 2 trial — with an oral PCSK9 inhibitor. Wow. I mean, we think of these drugs as injectables. What do you think of this one?
Oral PCSK9 Inhibitor and Gene Editing
Gibson: This was thought to be undruggable; it was thought that you could not develop an oral PCSK9 inhibitor. They screened about 10-16 different variants and found one that might be viable. They made some modifications, tested four different doses, dropped LDL-C by 41%-61% on top of a statin — very well tolerated.
Why is this important? I take a PCSK9 inhibitor. And, you know, it's the 7th of the month but I haven't taken my PCSK9 inhibitor because I forgot. My alarm went off but then I got busy and I forgot. Now with a daily drug, I'm probably more likely to remember because I take all my medicines in the morning. I don't miss them. It seems good to give a drug once a month, but in terms of implementation, in terms of behavior, in terms of habits, I've got to tell you, it's hard to remember that once-a-month injection.
Harrington: In the past we've talked about inclisiran, the once- or twice-a-year PCSK9 inhibitor. One of the things that I get excited about is the implementation science, and that's what you're referencing. We know that PCSK9 is a validated target. Here we have an oral drug. As you said, people struggled to find one and they found it. Now they've shown us that you can drop LDL-C in a highly predictable, dose-dependent way. But it's with a daily oral drug, not the IV injectable once- or twice-a-month drug. Now, what do we do?
The clinical outcome studies, as you know, are getting ready to launch. If they work out, then what we need to do is see how it stacks up from an implementation perspective, because your hypothesis is a reasonable one. But so is the hypothesis that less frequent dosing with good reminders can be done.
Gibson: I did a podcast yesterday with a group of people who are doing the digital pioneering of behavioral modification. I brought up my case and they said, "Well, we'd have to dig into why you're not taking the medicine." I said it's because one reminder is not enough. We need a closed-loop communication: "I told you to take your PCSK9 inhibitor," and I need to say, "I took my PCSK9 inhibitor." In the cath lab we don't just say, "Give the person aspirin"; we say, "I gave the patient the aspirin" so we're getting closed-loop communication.
Now there's a third alternative, and that is to treat someone one-and-done, genetically. That is what VERVE is doing; they're editing the PCSK9 gene and getting robust LDL-C reductions. It's a small study, about 10 patients, but an important proof of concept. They had a little bit of a rocky start; one patient had a heart attack the day after infusion and another patient died a month or two later — an interesting start to that area.
Harrington: That took us off the trip through the year, but I'm glad you brought it up because it's in the thematic area of lipid lowering, and in particular, PCSK9 inhibition. You probably also saw the clinical trial with an injectable antihypertensive drug that provides a prolonged antihypertensive effect.
Gibson: That has raised some questions in the device world. If every 6 months you go to your doc to get your blood pressure checked and you get this injection to keep it down, that could have big ripple effects on the device worlds.
Harrington: You're talking about renal denervation
Gibson: Yep.
Harrington: This goes back to the implementation science, and ultimately the policy pieces and the debates around reimbursement. It's what is going to be most effective for people. It's not good enough to have therapies that we know are efficacious; we need to know they're actually effective, and part of it is that people have to take it.
I'm a big believer in the notion that you don't have to go see your doc every 6 months for your antihypertensive; you could pop into your local grocery store or drugstore and get your blood pressure measured, and have somebody there give you an injection — monitor your blood pressure that way. Many interesting things that we're going to be excited by in the years ahead.
All right, fast-forward, Mike. We pop over to Amsterdam for ESC '23. The European Society of Cardiology picks some great cities to have their meetings, Amsterdam being one of those.
Gibson: I love Amsterdam, obviously, as a painter. I went to Rembrandt's house and to the Rembrandt Museum and the Van Gogh Museum. It's a very walkable city.
Harrington: ESC to me is one of the great meetings for clinician researchers. It's not a meeting where we see a lot of basic science. We see a lot of guidelines rollout, a lot of scientific statements, a lot of how-to sessions. I also love the way that they've designed their convention center; their sessions are almost like pop-ups in the hallway.
Gibson: They're also open to sessions at lunch; they'll provide lunch, so that works well. If there are two sessions going on at once in the open space, you can sometimes hear sound from both, which may not work well. I'm always a big fan of ESC. I think they get it right. It's very pragmatic and less textbook-y. It's "What do I do?"
Acoramidis and ATTR Cardiomyopathy
Harrington: It's the same with the ESC guidelines, right? They're much more about "What do I do?" And we could argue about how much the evidence is really studied, critiqued, etc., but I like the guidelines from ESC for that reason.
There are a couple of big trials I want to focus on. One of them is going to lead us into the AHA. First off, the results of a trial on transthyretin amyloid cardiomyopathy (ATTR). That session was early in the morning over the weekend, and it was packed.
Gibson: It should be — a progressive, fatal, expensive disease. We have tafamidis; it does a nice job of stabilizing this tetramer. But here's a new molecule, acoramidis, that does an even better job of stabilizing the tetramer.
The big question is, if it's more potent and more powerful, will it give you the same kind of outcomes that we're seeing in the Pfizer trial? The answer is yes. They looked at a win ratio of death, hospitalization, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and 6-minute walk distance, and the win ratio was 1.8. In other words, the drug won 1.8 times more often than the comparator. By the way, some people crossed over.
Harrington: I was going to ask you about that because the design is a placebo-controlled trial, but people crossed over.
Gibson: To open-label tafamidis at 12 months, so that's tough. At 30 months they won. The win ratio is being used more and more in trials, and it's important when you hear these results to look at each of the different components of the win ratio. Here, many of them were highly significantly beneficial. Death was numerically better. In fact, numerically it was 6.4% absolute reduction in death for a 25% relative reduction. It was numerically better for hospitalization, BNP, 6-minute walk — all highly, significantly reduced. When you're looking at the win ratio, always look at how often you hit those key endpoints up at the top. Between death and hospitalization, those accounted for 58% of the endpoints up at the top. In other words, this was not a trial that was just driven by BNP or 6-minute walk test; it was really a trial that was driven by hard endpoints. Very favorable reductions in mortality, I think.
Harrington: I'm glad that you brought up those individual points. Increasingly in the cardiovascular community, we're using the win ratio. It does allow you to combine different types of endpoints, as you've mentioned (biomarkers, intermediate endpoints, hard clinical endpoints), to get a sense — what I'll call globally — of the effect that the drug or therapeutic intervention is having on meaningful outcomes. Why are investigators using this more and more?
Gibson: From my perspective, it has made trials more pragmatic and you can get them done. I'll cite two examples. One was a bleeding trial that was going to take 600 patients; we got it down to about 120 patients.
Harrington: There are sample-size issues, for sure.
Gibson: It was much lower. An ST-segment elevation MI trial used to take 8000-10,000 patients. We're doing one with about 2500 patients now. Its going to be much more cost-effective. That's the good news.
The bad news is that people don't intuitively understand what a win ratio of 1.8 means. And the other problem is you're probably going to be underpowered on your traditional endpoints like death, MI, stroke. But the key thing is, are they all going in the right direction? And are they going in a magnitude that is consistent as well? You may not hit statistically, but numerically, are they going in the right direction with the right kind of relative risk reduction? This is a new way of interpreting things.
Harrington: This is a good example of why, when you look at a clinical trial result, you have to look at all of the data and look for consistency — even when you're looking at what I'm calling a traditional or conventional frequentist approach, and you look at your odds ratios of the individual components. You're not looking to see if one hits and one doesn't; you're looking to see whether there is consistency. Because biologically, if something works, most things are going to be consistent. They might be quantitatively a little bit different, but they're not going to be qualitatively different.
Gibson: One of the advantages here is that in a death, MI, stroke endpoint, those are all counted equally in a composite.
Harrington: I was going to ask you about that.
Gibson: You could have an MI that occurred before the death, but it's the MI that counts, not the death, in a traditional analysis. With a win ratio, death, the most important endpoint, is at the top. You're analyzing these things in a hierarchical fashion based upon how important they are. So there are some advantages of it, philosophically, pragmatically, clinically, and statistically.
GLP-1 Receptor Agonists: STEP-HFpEF and SELECT
Harrington: An advance in the field of treating amyloid and an advance in the clinical trials field.
All right. Let's move to a study that will help bridge us to the hottest news coming out of AHA, and that was the STEP-HFpEF trial. This was with semaglutide in heart failure with preserved ejection fraction (HFpEF). Wow.
The trial got some criticism that, well, of course if people lose weight then their heart failure syndrome is going to get better. But we have to put this into the broader context of the totality of the data. The GLP-1 receptor agonist drugs are showing us a whole new area of biology that has important clinical effects.
Gibson: People said, well, d'oh, you lose weight, then of course you feel better. It's more than that. Bob, I met yesterday with a brilliant investigator from the Brigham, Viviany Taqueti, and we walked through her data looking at HFpEF and obesity and how it relates to microvascular disease. When you have obesity and HFpEF, you have a lot of microvascular dysfunction, and she presented some very exciting work at AHA — I hate to jump ahead — that showed that at least with bariatric surgery, you improve microvascular dysfunction. So if this is a HFpEF population, it may not just be weight loss; it may be an improvement in microvascular dysfunction that's playing a big role in this improvement in symptoms.
Harrington: There's no question that the GLP-1 receptor is an important target now, and that the weight loss that accompanies use of these drugs is by itself important. But the ancillary clinical effects of better heart failure, fewer deaths, heart attacks, all of that creates this picture that this is a compelling group of agents that we still have a lot more to learn about, including some of the mechanistic issues.
Gibson: The event curves diverged very early; this isn't just reducing weight. We're reducing LDL-C, triglycerides, hemoglobin A1c, blood pressure. We're reducing C-reactive protein by 42% in one of the trials. I don't know the data yet, but there is a central action of these drugs in the central nervous system that curbs addictive behavior. In a poll I did on Twitter, 80% of people who are taking a drug said, "I drink less often" or "I stopped drinking," so it modifies every modifiable risk factor, possibly including smoking, and gives you a quick and early improvement in outcomes.
Harrington: And the cautionary tale is, remember, we studied other agents which suppress the pleasure center, the so-called cannabinoid receptor antagonists. I was on the DSMB for those trials, and we started to see the psychiatric disorders, particularly depression and unfortunately even a series of cases of suicide. We have to pay attention to that, as well as some of the longer-term GI side effects that certain patients have noted.
Gibson: There's dyspepsia that's going to occur in the United States with the $100 million price tag for this class of drugs. We've heard that story before with PCSK9 inhibitors. I think the good news is that many other agents are coming along — other dual inhibitors, even triple. Competition is good; hopefully it will drive down the price.
If you end up with metabolic syndrome, and you're over the age of 65 and have diabetes, renal insufficiency, or renal impairment and some heart failure, you are a $46,000-a-year Medicare beneficiary.
It's very expensive; over 10 years we're talking about a half million dollars to care for someone with metabolic syndrome. So, yes, the drugs will be expensive, but there are payment plans. Maybe you get a bonus if you make it to 65 and you don't have metabolic syndrome. We're going to have to figure out how to pay for it. Lower is better, but maybe earlier is better too.
Harrington: There are so many ancillary benefits of losing weight that include blood pressure control, glucose control, etc. This certainly seems to be a huge advance. We have to figure out not just the clinical issues but the policy issues, the reimbursement issues. I suspect that this time next year, when we do this review, we're going to be talking about this again.
All right, we've moved to AHA '23 in Philadelphia, another great place to have the meeting. I have a personal bias. Last time we were there was 2019. Just before the pandemic I was the AHA president. I love that convention center because it forces all of us into a common pathway. You see everybody as you walk through it. Your impressions of Philly?
Gibson: I think it was W.C. Fields who said, "I once spent a year in Philadelphia. I think it was on a Sunday." I do think it's a great city. It's a very soulful city with a lot of great food. It reminds me of the old Brigham pipe where there was only one hallway and you ended up passing by everyone, so I just sat in the hallway and did people-watching and conducted business there.
Harrington: They had musicians playing so there was this very peaceful atmosphere as you entered the convention center for the craziness of the day. I greatly enjoyed the AHA. Let's pick up semaglutide where we left off. The SELECT trial — a home run. It was the opening late-breaking clinical trial.
Gibson: A 20% reduction in death, MI, stroke in a nondiabetic population. I found the mortality data compelling. As a purist, you might say, well, they shouldn't have tested that, but anytime you have that endpoint, it's compelling. Again the curves diverged early, before you have substantial weight loss, hinting at the fact that a lot of this is risk-factor reduction — every single risk factor going down, and then you drive it all down quickly, like this. The events are reduced fairly early.
Harrington: And this gets back to your win ratio comment earlier, that everything was consistent here. I'm a bit of a clinical-trials methodologist, and to the credit of the investigators, they declared their hierarchical testing scheme and they stuck to it. They showed you the data, but they didn't start talking about significance and nonsignificance. I thought they were pretty fair.
It was a great session because in addition to the data, we had some other presentations on health equity issues, the policy issues, the reimbursement issues. We talked about the best of the ESC that was the best of AHA — when we bring everybody together from different areas of science and have a conversation.
Gibson: Exactly.
ORBITA-2
Harrington: Mike, let's do two more trials. ORBITA-2: the headlines were "ORBITA-2 Saves Interventional Cardiology." That was after a few years ago, when "ORBITA-1 Destroys Interventional Cardiology." Man, this was a terrific trial, and kudos to this group of investigators for doing them. They are hard trials to do. But are we really going to bury or resurrect the field on the basis of a couple hundred patients per trial?
Gibson: That's obviously a little hyped up. ORBITA-1 was extraordinarily well conducted. Not a big difference, or really no difference, in symptom improvement or exercise tolerance with PCI vs medical management. ORBITA-2 was a little different; it was testing more mechanistically the antianginal effects of PCI. They withdrew the antianginals, and when you start off tabula rasa with no antianginals, it turns out that PCI is a pretty good antianginal, probably about as good as a single agent. I think it's an important reminder that what we do is treat angina with this procedure, and it was effective.
Harrington: When we treat ST-elevation MI, we're saving lives. When we're treating coronary artery disease in a stable setting, we're improving symptoms and quality of life. And we just have to remember why we're doing things rather than spending our time castigating the procedure, which clearly has its role in different patient populations.
Gibson: Correct.
Factor XI Inhibition: AZALEA and OCEANIC-AF
Harrington: Let's talk about AZALEA. Now, in full disclosure, you and I are very involved with the factor XI inhibition field but not in the AZALEA trial. AZALEA showed that a factor XI inhibitor injectable can markedly reduce bleeding risk relative to other therapies. That's what we had hoped. Now we saw it.
Gibson: This really gave a lift to the entire field. We've seen lots of consistent results for the past 5 years. This class of drugs does reduce bleeding events, and the reduction here was so marked that it led to the DSMB stopping the trial prematurely. Now, what's interesting here is that this is a monoclonal antibody, a once-a-month injection, which makes people nervous — "Oh my gosh, am I going to be able to reverse it?" There was a significant 66% reduction in major clinically relevant bleeding; nonmajor bleeds had a 75% reduction; major bleeds, 97% reduction; and 93% reduction in GI bleeding. Now that's vs rivaroxaban, but it seems to be a much safer alternative.
Harrington: The DSMB stopped the trial because it had reached the conclusion that they had set out to reach, which was that they wanted to show what the safety effects were, and it showed it. No efficacy data here, though. And then a couple weeks after that, we see the premature cessation of another factor XI inhibitor — not the one that you and I are involved with, but another trial, OCEANIC-AF. We haven't seen the data yet, but the DSMB recommended stopping because of lack of efficacy — pointing out to me that, yes, we might get less bleeding, but we've got to do the bigger trials to show that you've got efficacy too.
Gibson: We were on a high. The whole class is looking great; this is a valid hypothesis. And then, boom! It was like a gut punch when the Bayer trial got stopped. I would urge everyone to refrain from commenting. People have said it must have been a big miss because it stopped so early. The trial was enrolling very, very rapidly. So reserve judgment on that.
People then began to go back and look at AZALEA and say, "Hold on, what about the efficacy?" It's inhibiting factor Xl 99%; was there an efficacy signal there? They began to look at the stroke data: 0.7% per 100 patient-years for rivaroxaban, but 1.3% for abelacimab — almost a doubling — and people were very concerned, saying, "Well, it looks like you see the same signal in AZALEA." That's probably not the case. I'm going to urge caution and ask people not to make those kinds of conclusions.
When you look at rivaroxaban in ROCKET-AF, it had a 1.34% per 100 patient-years risk for stroke. So the 0.7% in a very small study was probably an underestimation and the 1.34% in a very big study is much closer to what was seen for abelacimab in AZALEA. That probably gave the investigators comfort that they were not causing harm. But this is why we do big phase3 trials — to look at efficacy.
I want you to do a thought experiment. We've been down this road before with a safer alternative, and that was 30 mg edoxaban instead of 60 mg edoxaban. And do you know what happened? The 60 mg got approved because of the primary endpoint: stroke, ischemic stroke, and hemorrhagic stroke. But do you know what? The 30 mg edoxaban had a lower mortality — a lower rate of death or disabling stroke. The point is that the OCEANIC-AF trial got stopped early because it was inferior on the primary endpoint. But it's much more complicated. That endpoint does not include fatal bleeding, it doesn't include subdural bleeds, doesn't include ICH, doesn't include GI bleeds. So it's just the tip of the iceberg. We're going to have to look at the totality of the data. I hate to be critical of the design, but there's guidance on how to do a noninferiority trial in The New England Journal, saying you should not lump together endpoints that are going in the opposite direction. Ischemic stroke and hemorrhagic stroke are going in opposite directions, and if you have noninferiority with progressively increasing differences, that can neutralize and that drives you to noninferiority.
Harrington: There's a lot more work to do to understand this new area of biology with factor XI inhibition. We collectively as a community have a lot to learn. There's still some promise here; they clearly look to be safer when you look at some of the phase 2 data and when you look at something like AZALEA, but we've still got to show efficacy.
Gibson: What I will say in defense of the class is that the epidemiologic data are very clear. These people have much fewer venous thromboembolisms (VTEs) and stroke. The data are very consistent in the VTE space, that the drugs are safer and also more effective,
Harrington: More effective than current therapy. Yep, absolutely. That's the total knee replacement data with milvexian.
Gibson: I do think the class will be effective based upon that, but we will do the trials and see.
Harrington: All right, this has been a great roundup of the three big meetings: ACC, ESC, and AHA '23. I've been with my good friend and colleague, Mike Gibson. I hope you stick around and join us for part 2, where we're going to talk about a couple of the news and policy issues of cardiology. Mike, thanks, and stay tuned for the next presentations.
Gibson: Thanks, Bob.
Robert A. Harrington, MD, is the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and provost for medical affairs of Cornell University, as well as a former president of the American Heart Association. He cares deeply about the generation of evidence to guide clinical practice. When not focusing on medicine, Harrington dreams of being a radio commentator for the Boston Red Sox fan.
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