Top Cardiology Trials of 2022

This transcript has been edited for clarity.

Robert A. Harrington, MD: This is Bob Harrington from Stanford University, back for part 2 of the 2022 year in cardiology review. I'm here with my good friend and colleague, Dr Mike Gibson, from Boston. Mike is an interventional cardiologist at Beth Israel Deaconess. He's a professor of medicine at Harvard, and he's the CEO of the not-for-profit Baim Institute, an academic research institute.

Mike, in the first part, we were talking about doing clinical trials in China and being able to answer questions more rapidly. In this session, I'd like to run through a whole bunch of individual trials, agents, big questions, with the underlying theme of "Can we do things better?"

One of my favorite trials of the year tested a thing that I learned about by listening to people like Jim Januzzi and Gregg Fonarow, which is this notion of rapid escalation of guideline-directed medical therapy for heart failure. We were all taught to start your beta-blocker, add your MRA, add your ARB or ACE inhibitor, etc., which takes months and months. Now, there's a randomized trial that says people do better if you start it all at once.

STRONG-HF

C. Michael Gibson, MD: Yes, it's the STRONG-HF trial, which was done largely in Russia and Africa. I'm an interventional cardiologist. I think I'm an aggressive person, but then I get hesitant when all these heart failure doctors say, "No, start them all at once." It kind of scares me. That's what they're advocating. Get all those pillars started at once. They started three of those pillars — beta-blockers, MRAs, and angiotensin inhibitors — at once and they did better, but it required weekly visits to uptitrate over that next month.

That gets back to execution and infrastructure. It's a great idea, but can you do it?

Harrington: Do you have the team structure to do it? If we rely on the doctors to do it, I don't think it's going to get done. You have to have a structure that allows the doctor, if you will, to lead a team of diverse individuals with different types of backgrounds to make those calls every week to say, "Hey, how's your blood pressure? How are you feeling? Let's go up on the dose."

Gibson: Bob, there's also a biology lesson here. The human body is pretty amazing, and it has all these redundant pathways. If you block this, you increase this. Heart failure is a great example of that. You do better if you block multiple pathways with a low dose or starting dose than if you pick two pathways and go very high in the dosing. That's something we're going to see, I think, also over on the statin side of things.

Lipid Lowering and Lp(a)

Harrington: Let's talk about the statins. The thing that really got my attention this year is that now the lipid experts are saying it's not going to be one-drug therapy. You want to get people down to an LDL-C that's acceptable for their risk profile. You're going to need multiple-drug therapy, and guess what? Let's start them quickly so that you're not slowly titrating people up.

I was at a meeting this past weekend. I don't know if you coined the phrase "time is muscle" or if you came out of the research group where "time is muscle" was phrased, but now they're saying "time is plaque." What do you think about that?

Gibson: Clearly, lower is going to be better and longer is going to be better. In my own family, my two sons both went to their primary care docs and said, "I want to get on a statin in my thirties." They argued, gave them all the data, and they're both on statins now. I want to have my LDL-C down to somewhere around that of a hunter-gatherer, and the problem is, as you say, it takes many different shots on goal.

Statins lower your LDL-C, but they increase your cholesterol absorption. That's why we have ezetimibe. It blocks that escape pathway. There are similar things with LDL receptors and the PCSK9 inhibitors. All these things come together, kind of like the Tom Cruise line "You complete me."

Bob, I learned a hard lesson. I think we were going to talk about incidental findings and calcium scoring. I ended up having a calcium score of 1100. It was a real wakeup call because then, with an LDL-C of 70 and an HDL-C about the same, how in the world did this happen?

We looked and my Lp(a) was 2.75 times higher than normal. I was a skeptic about calcium scores, but I would not have known that had I not had that test done. Now I'm searching for ways to get my Lp(a) down. I think now that we fought the LDL battle, the next battle is going to be on some of these other markers, like Lp(a).

Harrington: There's a large amount of data about Lp(a) in some ways being the silent risk factor because people aren't measuring it routinely. We don't have a great way to treat it right now, but there are trials going on that are looking at lowering Lp(a). They're designed to see, first, can you do it biologically, safely, and effectively? Second, is that associated with improved clinical outcomes above and beyond statins? I absolutely agree with you.

The other thing that got my attention this past year is that we all are using the pooled risk equations, right? We have it built into our electronic health records. Your sons are a great example. Do they have to wait until they're 60 and their score goes up? Well, that's just been 30 more years of plaque deposition. Why not think about the accumulated lifetime risk? That's what people, I think, are starting to talk about.

Gibson: It's more than just cholesterol-years, where you multiply your LDL-C by your years. My LDL is really bad. My LDL is different from your LDL because I have an Lp(a). What I'm doing now for my kids is they're all going to get tested to see if they have the genetic variant as well.

About 20% of people are walking around with it. They don't know it. And they have a risk factor that's not modifiable by diet. We keep telling people to change their diet. Well, Lp(a) is not modifiable by that and it's not modifiable by statins or exercise. I think we're going to learn more about some of these other determinants. I do think getting this treated earlier is better.

DCP and TRANSFORM-HF Studies

Harrington: Mike, there were a couple of trials that got my attention, including furosemide vs torsemide in TRANSFORM-HF and then the diuretic comparison project on hydrochlorothiazide vs chlorthalidone. I think there are some good lessons there. Here are drugs we've used for decades and certain assumptions have been made. To your point, you don't really know unless you test them.

For example, people thought, well, maybe torsemide is a better diuretic when you're acutely congested with heart failure, and maybe hydrochlorothiazide is as good as chlorthalidone, even though the trials largely used chlorthalidone. Now we actually have clinical trial data.

Gibson: So much for experts. It really is important because this was recommended in the guidelines. Chlorthalidone was recommended over hydrochlorothiazide in the guidelines. When we put it to the test, another great hypothesis fell. That's why we do trials. These two studies are exactly why we do trials, and we're better for having done them.

Harrington: I agree with you. I love the hydrochlorothiazide vs chlorthalidone trial because of the way that it was done within the VA system in a pragmatic design. Kudos to our colleagues at the VA for being able to pull that off, and kudos to our colleagues in the Heart Failure Network for pulling off the furosemide trial.

Again, to your earlier point, Mike, networks, organization, and execution. A health system, the VA, and a heart failure research group answered the questions.

Gibson: The randomized trial may be one of the most important therapies we have.

Statin vs Supplements and Antiplatelets

Harrington: It clearly remains one of the most important advances in medical science.

The other thing that people love are supplements, Mike. I don't want to take a statin because I'm worried about those muscle things, but I'll take my various supplements. We had a trial that tested statins against a bunch of supplements. Guess which one won?

Gibson: Well, people are spending $270 billion a year on the nutraceutical industry just because they think it's organic and it's going to be better. When you compare a statin like rosuvastatin at a low dose vs things like fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice — six different kinds of natural therapies — it was no surprise. LDL lowering with the rosuvastatin was 30% better and this drug is costing $5 a month. I would hazard a guess that it may be just as inexpensive, and may be less expensive, than all those supplements. I hope we can get the message out about the nutraceutical industry.

Harrington: It needs to be exposed to the same rigor as many of the other things that people are taking for their health. You said one supplement after another fell by the wayside. As you know, I'm a big baseball fan. It reminded me that the 1999 All-Star Game in Fenway Park, where the great Pedro Martinez stood up and just mowed down — boom, one, boom, two, three, four — he struck out the four best hitters in the National League consecutively. Maybe Pedro and rosuvastatin have something in common.

Gibson: Maybe they do.

Harrington: Mike, a couple more things. In the area that you and I have spent much of the past 30 years working on, which is antithrombotic therapy, boy — just when you think you have this figured out, here come dual antiplatelet therapy and single antiplatelet therapy.

Gibson: You and I went through this journey where we were putting people on a million drugs when we put a stent in, including Coumadin. Then we breathed a sigh of relief when ticlopidine came along because we could sleep through the night. Aspirin plus ticlopidine seemed to allow people to not clot their stent off.

Harrington: Until they developed thrombotic thrombocytopenic purpura.

Gibson: Yes, there was a little issue there. Then clopidogrel and more potent antiplatelets came along. Then we thought, yeah, we need this for a year. Well, it turns out that no, we may not need it for a year. We've been backing down to 6 months, 3 months, 1 month, and then drop aspirin at hospital discharge.

There's number needed to treat (NNT) and number needed to harm (NNH). I call it NNB: number needed to blame. Interventional cardiologists don't want to get blamed for bleeding. Yes, it's going to be safer if you drop the aspirin. No surprise. The question has been, is it going to be just as effective? And most of the data suggest that it is as effective to drop it early.

The other thing we have to realize is that your platelets calm down. They're pretty angry at the time of the ACS, but they're going to get more and more quiescent over that year. We may need to match the dose or the intensity of what we're doing with the underlying disease.

Finally, the next big issue is that we've given aspirin for 50 years, but maybe thienopyridines are better than aspirin. Certainly, back in the '90s, we saw in some of those initial studies that clopidogrel was better than aspirin. We've now seen some more trials and meta-analyses that seem to suggest that a thienopyridine may be better for the long term than aspirin monotherapy. You're now going to see some comparisons of clopidogrel and ticagrelor to determine which one's going to be the better monotherapy there, building upon some of your PLATO trial data.

Yes, things are changing. On the other hand, there are also better aspirins now. There's a new aspirin that is phospholipid coated, so it doesn't damage the stomach as much. You see lower rates of ulcers and erosions. We see newer and newer therapies coming along. We assess all the new therapies and evolve, and it's just amazing to see the journey we've been on.

Harrington: I like how you say that over time things change. I always think about it as, when I'm making my antithrombotic decisions, there's the patient and their characteristics that include their risk of thrombotic events and their risk of bleeding. Then there's their coronary anatomy and whether it's diffuse disease, isolated disease, multivessel, single vessel. Then there's what we do to them.

I put in a single stent in the mid-RCA. That was a 4-mm stent that I post-dilated to 4.25. They have no other disease. Well, that's very different than I put in a 25-mm stent in both the LAD and the RCA. By the way, they have diffuse, nonobstructive disease.

Those are different situations, and I like the fact that people are now thinking about how to incorporate all of that over time. Your platelets are activated, your anatomy is what it is, but how do you incorporate that?

That brings me to my question for you, Mike, on antiplatelets. I've always thought — and you led these studies — that there's platelet activity, but there's also activation of the coagulation system. You've done great work with low-dose rivaroxaban that's never really caught on.

Antithrombins and Factor XI

Gibson: The platelets tend to calm down a bit, but what we do know is that it's a little bit like cholesterol. Some people have a higher level of thrombin generation, which is chronic. It doesn't calm down. It may go down a little bit, but we aren't treating that. One of the first things we do when someone comes in to the hospital is we give them heparin. Why aren't we doing something on the thrombin side chronically?

Of course, that's a whole new field that we're starting out with factor XI inhibition. Do I think that has potential to work? Yes, because we've shown multiple times now, at least three times now, that inhibiting thrombin improves outcomes in coronary atherosclerosis. I think we may see some success there.

Harrington: You and I are involved with several large trials with factor XI inhibition, and there is more than one factor XI inhibitor. I think that, in 2023, the cardiology world is going to see activity in factor XI. It may be a more effective anticoagulant, and it may be safer. Jeff Weitz talks about this decoupling of hemostatic bleeding risk from thrombotic risk, and factor XI may be uniquely positioned.

Gibson: When I told my son that we're going to start doing some factor XI studies, he just kind of rolled his eyes, as usual, and said, "Dad, why don't you stop these trials? Why don't you go look at God's randomized trial, Mendelian randomization?" He literally grabbed my hand, walked me to the computer, got on the UK Biobank, and within 5 minutes showed me all the Mendelian randomization data looking at factor XI deficiencies, like inhibition, and that they related to better lower rates of having venous thrombosis events and stroke.

There's a really good reason to think this will work. Over on the venous side, we do know that the holy grail there was met. Compared with enoxaparin, you had less venous events and you had less bleeding. We're leading trials of about 55,000 patients or more, looking at this in stroke, AFib, and ACS. The trials have been phase 2 studies. There's been no assessment of effectiveness yet, but safety looks to be good.

Harrington: I'm excited. I think this is a new frontier in antithrombotic therapy. Again, I'm with you, Mike, that we will continue to evolve in our understanding of the antiplatelet agents. I think we have an opportunity to better understand anticoagulant therapy over the long term in some areas where there's really an unmet need. Particularly, the secondary prevention of stroke data show that we really need some new therapies.

Gibson: We really need some new therapies. We really do. I think some of the phase 2 data looked really good. We may not win on small-vessel disease, but for big-vessel disease and TIA, some of the phase 2 data look pretty tantalizing.

Harrington: We've gone from very big issues that we've observed over the past year in the cardiology world to some very specific issues around trial findings and new trials coming. I want to thank you for joining me here.

My guest today has been my good friend and colleague, Mike Gibson, from Boston, an interventional cardiology professor at Harvard and the CEO of the Baim Institute, a not-for-profit academic research organization. Mike, thanks for joining me on Medscape Cardiology.

Gibson: See you in 2023.

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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