Top Cardiology Trials of 2020 in Review

; C. Michael Gibson, MD

Disclosures

December 15, 2020

This transcript has been edited for clarity.

Robert A. Harrington, MD: Hi this is Bob Harrington from Stanford University on theheart.org | Medscape Cardiology. For a number of years now, I've had the privilege of talking with my close friend and colleague, Michael Gibson, around this time to summarize the year in cardiology. A lot of times it's to talk about trials. Sometimes we try to bring in some policy issues or other things that seem to be resonating with our colleagues across the world of cardiovascular medicine.

Obviously, 2020 was a really difficult year for all of us, and first off I want to thank all of our frontline clinical workers. I also want to thank our researchers who have kept things going. Today, Mike and I are going to focus on all of the happenings in cardiovascular medicine that we found interesting outside of the COVID setting. We're going to do a second show on the COVID-related issues, but for this one we're going to stick to non-COVID issues. We're going to talk about lipids, antithrombotic therapy, and some new findings in heart failure. And maybe even wrap that around some of the lessons learned about doing research this past year, that we learned from COVID.

Let me introduce my close friend and colleague Dr Mike Gibson, Mike is a professor of medicine at Harvard Medical School, and he's an influential cardiologist at Beth Israel Deaconess Medical Center in Boston. He's also the CEO and director of the Baim Institute, an academic research organization. Mike, thanks for joining us here on theheart.org | Medscape Cardiology.

C. Michael Gibson, MD: I can't believe you keep having me back. How many years have we been doing this?

Harrington: It's at least 5 or 6 now. It's one of my highlights of the year to hear what you think about things we both learned over the years.

Gibson: Same here.

Harrington: Let's dive right into it, with some interesting findings in the lipids world. I'll bring up two topics, one of which is omega-3s. And the second is, do statins cause muscle pain? Let's jump into the lipid omega-3 story.

Gibson: It's been quite a rollercoaster ride this year, with the omega-3 fatty acids story. We all are familiar with the REDUCE-IT trial last year, which showed some positive results. And here in 2020, we get the STRENGTH trial. This is a trial of statin-treated patients who are at high cardiovascular risk; they had high triglyceride and low high-density lipoprotein cholesterol (HDL-C) levels, and they were treated with a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The trial showed no reduction in cardiac events. That was obviously very different to what we saw in the REDUCE-IT study. People have been scratching their heads. Some have pointed to differences in the placebo arms: In STRENGTH, they used corn oil as the placebo, and in REDUCE-IT they used mineral oil. Some people were concerned that the mineral oil may have reduced the absorption of the statins and, as a result, raised the low-density lipoprotein cholesterol (LDL-C) level; maybe that's the smoking gun.

But if you look at another trial of Vascepa (icosapent ethyl), where the placebo was nothing — it was truly inert because there was nothing given — that's the JELIS trial. In that study, with no mineral oil, they saw a 19% relative risk reduction, so the mineral-oil explanation does not really seem to hold water. When the US Food and Drug Administration (FDA) did their deep dive, they did not feel that that really held water. So we have two positive trials for Vascepa.

What I think is really interesting is that in REDUCE-IT, there was a relationship between higher levels of EPA and better outcomes. But they didn't see that relationship in STRENGTH. It makes you wonder: Is there something going on in the STRENGTH trial where the benefits of EPA may have been offset? The STRENGTH trial used DHA along with the EPA, and at this year's American Heart Association (AHA) meeting, there were some data showing that DHA may actually counter some of the benefits of EPA. In particular, the DHA was found to increase oxidized LDL-C and we know that's the really bad LDL, that may be associated with adverse outcomes. So it's a bit of a head-scratcher, there Bob.

Harrington: After the STRENGTH presentation, there was a lot of back and forth between commentators and investigators. You're getting to the essence of the issue, which is that we talk a lot about the class effects, but it really is important to look at the individual agents within a class because they are different molecular entities; they may not all work the same. Are you using the drugs in your patients with high triglycerides?

Gibson: I'm an interventional cardiologist, so I don't have a big clinical practice, but I am seeing it used more and I see patients on it.

Harrington: A lot of our preventive cardiology colleagues are beginning to use icosapent ethyl to try to drive down elevated triglycerides in patients who are otherwise well treated with statins and other drugs, who perhaps have already had a coronary event or have diffuse atherosclerotic disease. I think the story is going to play itself, out but it looks like REDUCE-IT is giving us information that we should be paying attention to.

Let's switch to something you and I were talking about offline, which is the whole notion of statin myopathies. We've been using statins now for more than 30 years, and a clinical conundrum is the group of patients who tell you, "You know, doc, since I started the statin, my muscles hurt."

Gibson: I didn't have muscle pain, but I started on simvastatin a few years back, and when I tried to get out of the car, I couldn't. I had to lift myself up by my arms, and I didn't know what was going on. Then I thought, maybe it's proximal muscle weakness in my legs from the statins. I did stop the drug, and it got better. Now I take atorvastatin, and I'm fine. When I saw the SAMSON trial stuff, it really blew my mind, because I was personally convinced that I was really developing myopathy.

Harrington: It really is interesting, isn't it? Did you check your creatine kinase (CK) levels at the time?

Gibson: I'm about the worst patient you can get, so I didn't.

Harrington: So that's a resounding no. We all see these patients who have some complaint of muscle weakness or muscle pain. And most of the time, this is without any evidence of elevated CK. If you take people off the drug, the symptoms get better; you put them on another statin, and sometimes it's better, sometimes it's not. You can find yourself running through the whole gamut of statins.

In the SAMSON trial, they compared statins not only against a placebo pill but also against taking nothing. And it looked as though there was some effect involved with the act of taking a pill. How did you interpret that?

Gibson: The placebo effect is powerful, but the nocebo effect is also powerful. It looks like there are some true cases of statin myopathy, but that seems to be the vast minority. Is that how you interpreted it?

Harrington: That was my takeaway. This was the most cleverly designed trial of the AHA Scientific Sessions for me. This was a well-designed small clinical trial, and kudos to the investigators for pulling it off.

Let's move over to an area you and I often spend a lot of our time thinking about, and that's antithrombotic therapy: antiplatelets, antithrombins. There was a series of studies in stable angina of crushing the adenosine diphosphate (ADP) inhibitors; we had TWILIGHT and TICO, and trials in transcatheter aortic valve replacement (TAVR). Do you want to dive in?

Gibson: You would think we would have moved beyond this field by now, but I was dumbfounded at how much research activity there is in the antiplatelet and antithrombin space. What's fascinating is that now these drugs are coming off patent, we're starting to see trials directly comparing drugs, and one example is this ALPHEUS trial.

You were involved in the PLATO study, which showed that ticagrelor was superior to clopidogrel in the setting of acute coronary syndromes (ACS). But what about stable angina? So the ALPHEUS investigators looked at 1900 stable angina patients undergoing percutaneous coronary intervention (PCI) who had one high-risk feature. Ticagrelor did what it always does and improved platelet inhibition. But there was no difference in periprocedural myocardial infarction (MI) or stent thrombosis — 1900 patients is a fair number of people. Now, there was no difference in major bleeding events, but there were more of those less severe BARC 1/BARC 2 bleeding events with ticagrelor. It was an open-label trial and people could be chronically on clopidogrel, but it looks like for patients with stable angina, clopidogrel may be sufficient. What was your take?

Harrington: This gets into the whole notion of risk stratification. For the group of patients who have an acute coronary event, we have clear data that more intensive platelet inhibition is better than less platelet intensive inhibition. But when you get into the stable angina realm, it might be that the risk is attenuated anyway — that the tradeoff of bleeding and ischemia may not be there with a more potent drug. It seems that we can risk-stratify appropriately and start to use the drugs that matter in a particular clinical setting. I think that's a good message.

Gibson: We never really latched on to the notion that platelets are really "angry" and activated in the setting of ACS, but they calm down over time. And we never match the intensity of antiplatelets to the intensity of the anger of the platelets. We've never really stepped down to 60 mg of ticagrelor; why not go down to 5 mg of prasugrel. why not go down to 50 mg of clopidogrel? We live in this binary world of stopping and starting, and you would think with all the discussion about tailoring therapy, we might do better.

Harrington: One of the things we really ought to be doing with antithrombotic therapy is establishing the best regimen at certain periods of time in the cycle of the disease. Coronary disease, as you know, is a cycle; it's a chronic disease that's punctuated by acute events. Are there periods in time where the antiplatelet effect is more important than the antithrombin effect, and vice versa? The challenges is that these are hard things to study in trials, and then you consider all the drugs and all of the strategy-type questions, and it becomes really unwieldy. But increasingly, we're seeing clever investigators, asking really clinically relevant questions for drugs that are largely off patent. Maybe it makes more sense at this time period to do the strategy trials.

Gibson: Yes.

Harrington: Now, I know you like nothing better than a good crushed pill.

Gibson: Bob, you've seen the picture that Duane Pinto and I took of the clopidogrel pills in the esophagus and the stomach during a PCI.

Harrington: I still use it in presentations.

Gibson: People thought it wasn't true. It is true; we actually filmed me with the pills on top of my chest to show that they really are radiopaque. They have titanium or something in them, but it's a reminder that there is delayed absorption of these drugs. When I poll physicians, 95% of doctors out there do not realize that if you give an opioid analgesic, the FDA label for all these drugs says that you should consider a parenteral drug, because the absorption is so horrible.

Now to get around this, we've had a world where we crushed ticagrelor or crushed prasugrel. When I look during a case, I see some poor soul sitting up with a bunch of white stuff around their mouth. I'm not sure how much is going in or how much is on the lips.

The COMPARE CRUSH trial looked at crushing prasugrel vs regular prasugrel, so this was not vs placebo. The crushed drug didn't improve ST resolution or open more arteries the setting of ST-segment elevation MI (STEMI). I want to remind the audience that these drugs really don't open up arteries. Remember that in the ATLANTIC trial, getting ticagrelor upstream didn't open arteries, or improve ST resolution instantly. In CLARITY, we did not see the clopidogrel open up arteries. These drugs do a good job of preventing rethrombosis, stent thrombosis, and reocclusion, but they're not going to get arteries open. This is in distinction to another class of drugs, the good old glycoprotein (GP) IIb/IIIa inhibitors, which do get a result. We're going to see some upstream approaches with subcutaneous GP IIb/IIIa inhibitors to try and get things opened up more quickly, but just in terms of the mechanism of action, it doesn't seem like the thienopyridines are going to do the trick.

Harrington: You and I have been involved in the trials of cangrelor, a short-acting intravenous (IV) ADP inhibitor. It makes no sense to me that you go to the trouble of crushing a drug — a series of maneuvers — when there's a short-acting IV drug available. If you really believe you need to get the drug on fast, all of the data from the CHAMPION PHOENIX trials that you and I were involved with show that a rapidly acting ADP inhibitor is a pretty good idea.

Gibson: We should also point out that this year, the European Society of Cardiology (ESC) changed the guidelines to make upstream thienopyridine therapy a class 3 contraindication in non-ST ACS if you're going to intervene quickly or if you don't know the anatomy.

Harrington: What that has told me is that once you know the anatomy and you've decided, for example, whether you're going to do intervention or not, you might want to start an ADP inhibitor if you're going to do your procedure right away. The data from CHAMPION PHOENIX are pretty compelling. Getting the rapidly acting ADP inhibitor on board at that time, but waiting until you see the anatomy and then having a drug rapidly available, seems to make good sense.

Gibson: And there are going to be some drugs coming down the pike that will reverse some of these drugs, such as ticagrelor.

Harrington: Well, let's talk about ticagrelor. There were a couple of trials: TWILIGHT and TICO. Put them together, and that maybe give us your bottom line.

Gibson: The bottom line is that in TWILIGHT, we gave people 3 months of dual antiplatelet therapy (DAPT) and then randomized them to ticagrelor monotherapy vs staying on DAPT and found that there was less bleeding with ticagrelor monotherapy, and no increase in ischemic events. Now, we didn't include patients with STEMI in TWILIGHT. The TICO STEMI paper was a subgroup analysis from the overall TICO trial. In 1100 patients with STEMI, they found a threefold reduction in bleeding (0.9% vs 2.9%) if you just give ticagrelor monotherapy after 3 months instead of giving DAPT, and there was no difference in ischemic events (2.7% vs 2.5%). So it does confirm the results of TWILIGHT. Aspirin isn't a great antiplatelet. It's not as good as the thienopyridines in terms of its potency, and it does cause gastric erosion.

Harrington: Not many years ago, aspirin was the foundational pillar that you couldn't move, and now a whole series of trials has raised questions about that. Even if we think about the atrial fibrillation (AF) trials with triple therapy, getting rid of the aspirin in many cases looks to be a good idea, doesn't it?

Gibson: The data are really firmed up now, with thousands of patients, that dual therapy with a thienopyridine and a novel oral anticoagulant (NOAC) is probably the way to go and get rid of aspirin. What's fascinating to me philosophically, Bob, is that we just kept adding on top of aspirin; we never replaced aspirin. We asked, does this drug add anything to aspirin: Here's what we never did ask: Does aspirin add anything to this new better drug?

Harrington: Remember WOEST? That was dropping the aspirin.

Gibson: Exactly. For 20 years, we just kept piling things on.

Harrington: Speaking of aspirin, let's talk about the POPular TAVI trial, which was an interesting study, moving out of the coronaries and into the valve realm.

Gibson: There are two parts to POPular TAVI. One was cohort B; these were people on chronic oral anticoagulation. If you got rid of the clopidogrel, you reduced bleeding, by 41% and you didn't increase your thrombotic events. I think people were a little astonished by the safety, with no thrombotic events. Then in cohort A, for patients not on anticoagulants, they compared aspirin alone vs DAPT with clopidogrel for 3 months in 690 people. Keep in mind, these are old people. These are 80-year-olds, and the bleeding went down as you would expect, from 26.6% down to 15% with aspirin alone and no difference in ischemic outcomes (9.9% vs 9.7%). Less is more once again.

Harrington: An important clinically valuable set of information.

Mike, I want to close with the area that's had the most action, if you will, this year, which is heart failure. We've got the sodium-glucose co-transporter 2 (SGLT2) inhibitors; we've got the guanine cyclase inhibitors; and we've got the muscle-active drug, omecamtiv. So that's EMPEROR-Reduced, VICTORIA, and GALACTIC-HF. Give us the gestalt, Mike: How does this fit into the paradigm of caring for the patient with heart failure?

Gibson: I would say these have been the biggest 2 years for heart failure. We hadn't had a lot of improvements in focusing on left ventricular (LV) contractility — things like milrinone that increase mortality. Now we highlighted a few new pathways targeting the myocardium. The old way was the classic calcitropes; those had deleterious effects. The newer class is what we're calling myotropes, which improve the energetics of the heart — drugs such as perhexiline and ranolazine. As you mentioned, one of the leading theories about the SGLT2 inhibitors is that they improve energetics, and now a new third class of myotropes are acting on the sarcomere.

Last year, we had DAPA-HF which showed improved outcomes. Now this year, we had EMPEROR-Reduced. Another SGLT2 inhibitor in over 7000 patients also showing improved outcomes. In DAPA-HF, there was a reduction in death that we didn't see with empagliflozin, although it was a smaller trial. The concordance of data for this class of drugs suggests that the SGLT2 inhibitors should be part of the foundational therapy.

There was a new kid on the block, sotagliflozin, studied in SOLOIST. That trial was stopped early. It's a dual SGLT1 and 2 inhibitor, and it too reduced death and recurrent hospitalization. So we have three good shots on goal with this class of drugs.

You mentioned another approach: the soluble guanylate cyclase (sGC) stimulator vericiguat, which directly enhances cyclic guanosine monophosphate (GMP). In the VICTORIA trial, it reduced cardiovascular death or first hospitalization by 10%, with no difference in death. And then finally, the last one that you mentioned, the new myotrope omecamtiv makes it easier for the myosin to pull on the actin like a rope. That drug didn't increase oxygen demand or calcium influx; it prolonged ejection time and increased stroke volume, so it does good things in terms of the mechanics. And like the other drugs, it also reduced death or hospitalization or urgent visit, but no benefit was seen on mortality. All of these new drugs seem to reduce death and hospitalization, but dapagliflozin is standing out as the one that reduced mortality.

Harrington: The SGLT2 inhibitors will be truly foundational because of the very hard clinical endpoint benefit, and some of the other drugs look like they may have a niche effect on top of what will now be multidrug therapy with sacubitril valsartan, beta-blockers, mineralocorticoid receptor antagonism, and SGLT2 inhibition. It really is very aggressive foundational therapy that makes the difference. I look forward to seeing the next version of the heart failure guidelines to see how our colleagues in that world sort all of this out — what drugs, what patients, when?

Gibson: That sounds more like a meal plan than anything. It's a lot of drugs to take.

Harrington: It's a lot of drugs, and some of them are generically available but not all, and we're going to have to think in terms of societal cost-effectiveness. But if you start reducing hospitalization, you do save money, don't you?

Gibson: You do. It really is a testament to all the different pathways the body has to compensate for things. You have to block all these compensatory pathways to make an impact. Life is full of multivariate biologies.

Harrington: Kudos to our colleagues in the heart failure world for leading some fantastic trials. Well, Mike, as always, this exercise of thinking about the year has been fun with you. I think it's also been incredibly impressive that the science continues, despite all the challenges with COVID.

You and I are going to have another session where we talk about the COVID-related lessons for cardiologists, but do you want to try to put some context to the science going on while COVID is affecting us in so many different ways?

Gibson: It really amazes me that we have been able to continue to do trials in the midst of all this, and it's a real credit to the investigators. I have to also say though, sadly, we lost two out of 50 country leaders in one of our trials. One of them, Tony Gershlick recently died due to COVID. So, we've had some hits. We've also had sites close down permanently as a result of COVID. But despite that, the science has continued in the cardiovascular space. It slowed down when we hit the shutdown. But now we're plugging away. It's a real testament to the doctors; the nurses; and, most important, the patients, for agreeing to participate.

Harrington: I want to thank you, Mike, for joining us. This has been a terrific review of 2020 and what's gone on in cardiovascular science and medicine. My guest has been Dr Mike Gibson from the Beth Israel Deaconess Medical Center in Boston, where he's an interventional cardiologist; from Harvard Medical School, where he is a professor of medicine; and the Baim Institute —he is the director and CEO of that academic research organization. Thanks, Mike, for joining us on theheart.org | Medscape Cardiology.

Gibson: Thanks, Bob.

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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