COMMENTARY

Cardiology 2019: Top Trials in Review

ISCHEMIA, COMPLETE, ORION, REDUCE-IT, AUGUSTUS, TWILIGHT

; C. Michael Gibson, MD

Disclosures

December 17, 2019

Robert A. Harrington, MD: Hi. This is Bob Harrington from Stanford University, here on theheart.org and Medscape Cardiology. It's time for our annual review of the hot issues in clinical research that have affected or influenced cardiovascular medicine in 2019.

As we've done in the past couple of years, I'm pleased and honored to be joined by my good friend and colleague, Dr Mike Gibson. Mike is a professor of medicine at Harvard Medical School, an interventional cardiologist at the Beth Israel Deaconess Medical Center in Boston, and he serves as the director of the Baim Institute. Mike, thanks for joining us here on Medscape Cardiology.

C. Michael Gibson, MD: Always a highlight of the year to be back.

Harrington: People wondered if any new things were coming out, and 2019 certainly seemed to prove that. We have a lot of new things focusing on strategy to talk about, as well as some new drugs.

Gibson: We do. When we were at the European Society of Cardiology Congress, I said, "Wow, cardiology is back." It's like we're back in the '90s again. It's exciting, with results of highly anticipated trials and some new drugs.

Harrington: It's going to be a fun conversation. In this first segment, we will talk about revascularization in the management of coronary disease, lipids, and antithrombotics.

The ISCHEMIA Trial

Harrington: Certainly one of the most hotly anticipated and awaited trials of the year was the ISCHEMIA trial, which you and I know well. You served on the Data and Safety Monitoring Board (DSMB) through the National Heart, Lung, and Blood Institute (NHLBI) and I served on the executive committee of the trial. You had the interesting perspective of observing the data over the many years, so why don't you describe the trial and then we will discuss it.

Gibson: It was highly anticipated, but at the end of the day I was not all that surprised. We knew that percutaneous coronary intervention (PCI) improved symptoms, but in the stable setting it probably was not going to reduce death or heart attack, and that is what we saw here. Of course, this trial builds upon what we knew from COURAGE which was done back in 2007. It was done in an era when we largely had bare metal stents; we now have drug-eluting stents and different pharmacotherapy as well. COURAGE had 2200-plus patients randomized after angiography and found no difference in death or nonfatal myocardial infarction (MI). People said, "Maybe that biased the results a bit." There was a fair amount of crossover in the study.

Importantly, back in 2014, a substudy said that if you had more ischemia, you might have more benefit, and that laid the groundwork for the ISCHEMIA trial comparing an invasive strategy with optimal medical therapy. Everyone got optimal medical therapy. It's important to note here for the audience that this is in stable heart disease, not acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI); ejection fractions were above 35%. Participants had to have moderate to severe ischemia that was greater than 10% on nuclear scan, greater than three segments on echo, or greater than 12% on MRI. It's also very important to note that this study excluded people with left main disease. CT was used to diagnose left main. If you were in the invasive group you underwent angiography and had PCI or coronary artery bypass graft surgery (CABG), and if you were in the medical therapy group, you only underwent angiography for failure of medical therapy. It was a big trial with 5000-plus patients followed up for 3.3 years.

What was interesting to me was the angina frequency, and I will circle back to this: 34% of participants had no angina. If revascularization reduces angina as its only benefit, you've got to wonder about the third of people out there who are getting nuclear stress test on an annual basis as a screening test. Is that really viable moving forward? There was a fair amount of crossover; 28% from the medical group ended up undergoing catheterization. The primary outcome was cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. There was a bit of a tempest in a teapot about the change in the primary endpoint. It's important to note that this change was prespecified prior to the initiation of the trial in anticipation of a lower-than-expected event rate. I think it was perfectly reasonable to make that change. The primary outcome occurred in 13.3% of the routine invasive group and 15.5% of the medical therapy group, and the difference was not statistically significant.

After staring at this over the years, this is what was interesting, Bob. Look at the Kaplan-Meier figure from this study and you will see that in the first 6 months of that first year, there was harm. There was about a 2% absolute increase in risk in the first 6 months with the invasive strategy. You can imagine my thoughts looking at the early data and what was going on in that early period of the study.

The lines cross over at around 2 years so that those in the invasive strategy group start to have lower events. So, the rule that you have to have proportional or constant hazards throughout the study was violated and some of the traditional statistical techniques may not be appropriate.

The secondary outcome of death or MI occurred in 11% of the invasive group and 13.9% in the medical therapy group, so, not different. All-cause death was nearly superimposable. Periprocedural MI was about 2.9 times higher with the invasive strategy, obviously. But on the other hand, spontaneous MI, as you might expect, was lower in the invasive strategy by about 33%. When you put it all together, those two balance out and there is no difference in those hard outcomes.

Quality of life, though, was better in the interventional group, but this improvement was seen in those with either daily, weekly, or monthly angina. It wasn't seen in those people without angina. There was really no heterogeneity in the treatment effect. It didn't matter how much ischemia you had; the results were similar, with very low rates of events in the trial. The odds of seeing a difference greater than 10% in the study were less than 10% using a Bayesian analysis, so it's highly unlikely that we missed a signal that was bigger than a 10% relative benefit.

If you have no symptoms, we can't make you less symptomatic.

It was unblinded and there was no sham procedure. Again, this only applies to stable patients; it doesn't apply to ACS patients. The benefit was in symptomatic patients with no left main disease, no heart failure. I think the losers here are those people doing a lot of annual screening surveillance stress tests in asymptomatic patients. I'm not sure that is going to yield a clinical benefit because there was no benefit in death or MI in the hard outcomes, and the only benefit was in symptoms. If you have no symptoms, we can't make you less symptomatic.

Harrington: You've summarized it well. I had certain beliefs going into this, as did you, but now we have data that cement those observations. When it comes to a medical procedure or a medical therapy, I ask, "Is it going to make my patient live longer, feel better, or avoid unpleasant experiences like rehospitalization, heart attacks, heart failure episodes, etc.?" According to ISCHEMIA, the answer to whether revascularization will help you live longer is no. The answer for decreased heart attacks, rehospitalization, etc., is no. The answer for feel better is yes. But you can only feel better if you felt bad to begin with, as you've said. So it does really say that the asymptomatic patient, even with an abnormal stress test, can be medically managed.

I also took away a couple of other things. It was an encouraging sign that we still have some improvement to make in medical therapy, despite the fact that it was pretty good in ISCHEMIA. I think you've nicely said that this raises a lot of questions around the role of imaging. One of my pre-test biases was that if you had a lot of ischemia or if you had multivessel disease, you were more likely to benefit from a revascularization approach than medical therapy alone, and that does not appear to be true. So that changes how I think about this group of patients a little bit.

Like you, I have raised questions about the role of imaging. I like stress testing for a lot of reasons, in terms of how long could they exercise, what heart rate did they achieve, what happened to their blood pressure during exercise. This helps me tailor medical therapy. But one key question is, do you need to get imaging in this group of patients to accompany stress testing or are the physiologic parameters enough? That is an important discussion to have.

Finally, do you think that people need a cardiac CT to rule out left main disease or to establish the diagnosis of nonobstructive disease?

Gibson: One of the winners here was the CT. I put a poll up on Twitter that was interesting. People seem to be gravitating back toward the anatomic assessment with CT and pulling away from the functional or physiologic assessment on the ischemia side. That was an interesting pivot in terms of people's perspective. It wasn't a big difference, but the anatomic assessment CT had pulled ahead.

It's not all about bad plumbing; a lot of ischemia is mediated by the downstream microvasculature.

Harrington: It may not be a bad approach to say to your patient with stable ischemic heart disease, "Let's get a cardiac CT to rule out left main disease, and assuming there is no left main disease, let's embark upon a really aggressive course of medical therapy. If your symptoms go away and you're doing well, let's manage it that way." Would that be reasonable, Mike?

Gibson: I think so. I've always been a fan of the microvasculature, and it's interesting to see that being increasingly recognized as playing a big role. It's not all about bad plumbing; a lot of ischemia is mediated by the downstream microvasculature. If I had to guess—and I know some studies are coming along—you are going to see a resurgence and interest in treating the microvasculature, not the epicardial vessels, particularly in women with nonobstructive disease.

Harrington: A parallel substudy funded by NHLBI is looking at that group of patients who ended up having nonobstructive disease and were not randomized. More to come on that group. I agree with you, and I'm glad you brought it up.

COMPLETE Revascularization

Harrington: Let's move to the COMPLETE study. The question in STEMI has always been, what do you do when you open the culprit and you see other disease? The guidelines have told us that unless they are in cardiogenic shock, you just handle the culprit and leave them alone. Get out of the lab and don't treat the others at that time or during that hospitalization. This study turns that around, doesn't it?

Gibson: I wrote the section in UpToDate on this, and when you look at CULPRIT-SHOCK, running around and dilating all the vessels was actually a bad idea. So things have gravitated toward a contraindication in treating beyond the culprit artery in the shock setting, contrary to the clinical practice. There were some small, modest-sized trials and a lot of observational data saying we should be dilating the nonculprit vessels, but they were highly confounded. COMPLETE was a much larger study with 4000-plus patients at 140 centers. It was open-label, but the outcomes were assessed blindly. There were two strategies. Completely revascularize—even if you did not think there was ischemia, you would revascularize a nonculprit artery if it was over 70% blocked. In an intermediate lesion in the 50%-60% range, you did a fractional flow reserve (FFR), and if that was positive you revascularized. The other strategy was to leave everything else alone and only revascularize the culprit vessel.

For about two thirds of the patients, the nonculprit revascularization was done on the first day during the initial hospital stay. Importantly, about a third of the patients came back later for the procedure at about 23 days. There was about 4% crossover, so not a lot. About three quarters of people had just one other vessel treated. The primary outcome of death from cardiovascular disease or new MI was 7.8% in the complete revascularization group and 10.5% in the culprit-only group. That is a pretty big absolute risk reduction at 2.7%, so you would only need to do about 30 procedures to prevent one of those bad events.

What was interesting is that the benefit was driven by a reduction in new MI, but obviously not in the culprit vessel. It was over in the nonculprit territories and it was late. It wasn't immediate; it was later on during follow-up. There was no difference in death. When you look at the composite of MI or death and revascularization, it's 16.7% in the culprit-only group versus 8.9% with complete revascularization. There was no difference whether you did the complete revascularization early or late, and there was no difference in bleeding, stroke, and stent thrombosis. To be honest, I was surprised. I thought after CULPRIT-SHOCK it was not going to be a good idea to do complete revascularization, but I guess I've changed my mind seeing the results here.

Harrington: Maybe this builds on the comment you made about the ISCHEMIA trial and the world moving back to anatomy. Anatomy seems to be pretty important. It seems to be pretty important to treat the lesions that appeared angiographically significant because the COMPLETE results looked pretty compelling.

Gibson: I agree. It may not be that we are improving ischemia in this study; it may be that STEMI is a marker of plaque rupture. And if you have all of these other lesions everywhere else, you are clearly someone at risk for more plaque rupture. Perhaps what we're doing is preventing that plaque rupture. I'm not sure it's an ischemic benefit but more of a plaque rupture prevention strategy which bears fruit late, interestingly enough.

Harrington: This takes us back to the past, right? Years ago, Rick Kuntz talked about whether you should be stenting more of a blood vessel in order to prevent later events. It's interesting that with improved stent and medical technologies, older ideas may actually come back to the forefront.

Gibson: It was in the mid- to late '90s when I showed that we measured in thousands of people the distance from the ostium to the lesion, and most of these lesions that behaved poorly were pretty proximal.

Harrington: I remember those papers.

Gibson: That set the stage for the idea that maybe we should be passivating the lesion and preemptively stenting. That never really took off but it's an interesting concept.

Inclisiran and Lipids

Harrington: Let's move from revascularization to preventive cardiology. We said at the outset that it's an exciting year not just for confirmation of strategies like ISCHEMIA and COMPLETE but also for new drugs. Let's first talk about the ORION trials with inclisiran. There is a series of trials but we don't have to go through them. The concept is interesting. We know that PCSK9 inhibition with antibody-based strategies improves clinical outcomes, but now we have a whole new way of delivering a PCSK9 inhibitor. You want to talk a little bit about that?

Gibson: I would not even call it the LDL cholesterol (LDL-C) hypothesis anymore and I may inflame people by saying that. The LDL-C and outcomes relationship was really rooted in statin therapy, and the big question was, is it just about LDL-C or is it about the way you get your LDL-C lowered? We learned from IMPROVE-IT that with a nonstatin drug like ezetimibe, it fell on that curve. In other words, it's not about the drug; it's about the LDL-C lowering.

Of course, another class of drugs has come along, the PCSK9 inhibitors, which lower LDL-C in a different way and have yielded benefit on top of aggressive LDL-C lowering with statins. That is great but the two drugs so far are antibodies. They tend to require dosing either every other week or once a month, so they require a lot of injections. And the cost has been very high—the cost of goods when you have an antibody is quite high.

Inclisiran is very exciting, not just because it's a drug that lowers LDL-C, but because it's in a whole new class of drugs. It's a small interfering RNA (siRNA)-based technology. A way to think about this is that antibodies "mop up" all of the excess PCSK9 while inclisiran turns off the tap and prevents the sink from spilling over. It's a different way of downregulating the amount of PCSK9 in your body.

How far do we back up the truck in terms of primary prevention?

Here's the exciting thing: The drug has a long biologic half-life, and you can inject it twice a year and get an LDL-C lowering of about 55%-58%, according to all the studies. I have not seen this published yet, but I heard that if you inject once a year, you can still achieve LDL-C lowering of 45%-48%. I want to see that number published. But Bob, it would be amazing to be able to have people come either twice a year or once a year and achieve that kind of LDL-C lowering on top of statin therapy. From a public health perspective, it's kind of amazing.

Harrington: It's really amazing, and with the recent data we saw at the American Heart Association, we're starting to see longer-term safety data which had been one of the remaining questions with the siRNA approach. Of course, we don't have the clinical outcomes yet—that is certainly a cautionary tale. It is a different mechanism of inhibiting PCSK9, but we know that PCSK9 is a validated target at this point. Clinical outcome studies are being done, and the conservative trialist in me says we have to await those, but this could be a major change in how we think from a public health perspective.

Gibson: For safety, we now have 3000 patient-years–plus worth of exposure. It looks like there are no liver side effects or other toxicity, so that is good. My son is a quantitative genomicist and he always teases me. "Dad, why are you doing all those trials? Just use Mendelian randomization to pick your targets." And he was right on this one. Nature does randomized trials, and if you are one of those people that got randomized naturally to having genes that reduce PCSK9 over a lifetime of exposure, not a couple of years, you have a dramatic reduction in CV risk.

The next question that my son raised was, "I'm in my thirties; should I be taking statins, given the lifetime exposure [risk to coronary artery disease]? Should I be taking a PCSK9, given the lifetime exposure risk to coronary artery disease?" One of the questions will become, how far do we back up the truck in terms of primary prevention rather than just secondary prevention?

Harrington: That is a great question, and this certainly is a success story for the folks using genetically guided drug discovery and development. I'm not ready to exchange randomized clinical trial for Mendelian randomization. We could have a whole discussion about differences between a randomized clinical trial and Mendelian randomization, but let's move on.

Gibson: I'll let you argue with my son on that.

Harrington: I am not arguing with your son; he is much smarter than I ever will be. Much smarter than you and I together will ever be.

Gibson: Correct.

Omega-3 Fatty Acids: REDUCE-IT

Harrington: Let's talk about triglycerides and REDUCE-IT.

Gibson: We just talked about how it's not about the drug, it's about the LDL-C. There are non-LDL-C ways of improving outcomes potentially. Triglycerides have always been identified as a risk factor but we've never known whether modifying triglycerides would really improve outcomes. One class of drugs that does improve triglycerides is the fish oils. There are a bunch of different types of fish oil. The one studied in REDUCE-IT is very specific: It's a highly purified form of eicosapentaenoic acid (EPA) and has been shown to reduce triglycerides. This study looked to see if the label could be expanded to include a reduction in hard outcomes like death or MI. There were a lot of other studies before this, but they used over-the-counter fish oils, some nonpurified, and with docosahexaenoic acid (DHA). I practiced saying that all morning, Bob.

Harrington: Good job.

Gibson: This study was preceded by a study in about 18,000 Japanese patients which showed a 19% reduction in events. This was not a study of Vascepa (icosapent ethyl) alone; to be enrolled, you had to have a triglyceride level between 150 and 499 mg/dL and you had to be on statins. It was a randomized, double-blind, placebo-controlled study. Mineral oil was used as the placebo, which matched the consistency and color of the EPA. There have been questions raised about that, which we will get back to in a minute. Lots of centers around the world participated. After 4.9 years of follow-up, Vascepa did what it was supposed to do—it lowered triglycerides by 18.3%.

What is interesting is that LDL-C went up 3.1% in the Vascepa group and 10.2% in the mineral oil placebo group. People said, "Aha, the mineral oil blocked the absorption of the statin and that is why Vascepa won." But at the end of the day, that is probably not the case. Vascepa did lower the prespecified primary endpoint from 22% to 7.2%. It lowered death, MI, and stroke from 14.8% down to 11.2%—again, on top of statins.

A cardiologist and chief or chairman of medicine at Mass General who I used to work with out at the West Roxbury Veteran's Affairs Hospital showed that these drugs reduced arrhythmias in dogs, and in my mind it was not surprising that adjudicated sudden death and cardiac arrest were reduced.

Surprisingly, there was a slightly higher rate of atrial fibrillation (AF), mostly in people who had AF in the past (5.3% vs 3.9%), and there was a little more bleeding with EPA. These are the kinds of issues that will need to be dealt with on the label. The Food and Drug Administration (FDA) advisory panel met and examined the issue of the mineral oil and the small rise in LDL-C. This rise does not seem to be sufficient to account for the 25% reduction in events. The advisory panel recommended that the FDA label should be expanded, by a vote of 16 to 0. We may have another tool at our disposal.

I think this is going to be a new tool in the tool chest for our patients with hypertriglyceridemia.

Harrington: You summarized it well and provided the key issues for me. This is a field where there had been a lot more hype and hope than definitive data, but now we have a well-designed, well-carried-out study with clear clinical outcome benefits. The question about the mineral oil and LDL-C was something I certainly had discussed when I first saw the results. You did not mention this, but C-reactive protein also went up.

Gibson: A lot—by about 30%.

Harrington: Yes, there were some inflammatory markers, so the question was whether this was an unfair test of an active placebo that was potentially deleterious against the drug. As you have noted, a lot of analyses were done that said even an active non-inert placebo could not account for the difference between them, and the advisory committee voted to extend the label. I agree; I think this is going to be a new tool in the tool chest for our patients with hypertriglyceridemia. An important trial of 2019.

AUGUSTUS and TWILIGHT

Harrington: Let's finish with a conversation on antithrombotics, an area that you and I have spent much of the past 30 years working on. I want to focus on AUGUSTUS and TWILIGHT. Let's do AUGUSTUS first. This is one of many studies now that has been done to understand the optimal combination of antithrombotic therapy in that group of patients who have need for both dual antiplatelet therapy (DAPT) and anticoagulant. Can we peel away one of the antiplatelet agents and still give patients good anti-ischemic protection while protecting them against the risk for stroke with their AF? You have been involved with this field, and I think the results of AUGUSTUS are very consistent with other studies. How did you interpret AUGUSTUS?

Gibson: The results are entirely consistent. There are about 2.8 million ways to combine all these drugs, and we're trying to bring some order to all this madness. It looks like AUGUSTUS shows what all of the other studies show, namely that combining a non–vitamin K oral anticoagulant (NOAC) with a thienopyridine reduces the risk of bleeding—clearly—compared to any kind of form of triple therapy. And by triple therapy I mean DAPT plus an anticoagulant, often warfarin.

We've done meta-analyses now, and we've done a lot of different analyses lumping together all the data. The message is very consistent: You get a significant reduction in bleeding. When you look at death, MI, and stroke, the point estimate is 1.0—there is no difference when you lump all the studies together in a bivariate analysis. The upper limit of that confidence interval is only 1.13, so we are fairly confident at this point that there is no excess risk for ischemic events when you largely drop aspirin from these studies and continue on with just an anticoagulant and a thienopyridine.

Harrington: Yes, and we have struggled for a long time with that important clinical observation of what do you do? How do you risk-stratify and put them on triple therapy for the shortest period of time as possible? We now have good evidence from across studies. This is one where you have to look at the totality of the data. The NOAC plus the P2Y12 inhibitor appears to be the way to go.

Another trial that really challenged the notion of combination therapy versus monotherapy was TWILIGHT, which ended up being one of the big hits of the Transcatheter Cardiovascular Therapeutics (TCT) 2019 conference. You want to talk about TWILIGHT?

Gibson: It's fascinating. When you and I were younger, remember what we used to do? We used to put in 10 French sheaths for atherectomy and then put in a stent. We would give dextran, heparin, warfarin, aspirin, and dipyridamole. It was insane.

Harrington: And leave the sheath in for days.

Gibson: Then came along STARS, and ticlopidine and aspirin turned out to be much better than all of that in reducing bleeding and looked to have very good ischemic outcomes as well. Of course, ticlopidine was replaced by clopidogrel. It is fascinating to me because over the next two decades we said, "Aspirin is foundational therapy, but do all of these new things, like clopidogrel, prasugrel, and ticagrelor, add to aspirin?" And the answer was yes. We never said, "Let's say that the thienopyridines are better antiplatelets and let's see if aspirin adds anything to them."

Cardiology is back.

Finally, for the first time on the cardiovascular side, we did that. TWILIGHT asked, "Does aspirin add anything to ticagrelor alone?" That is the way I've tried to characterize this. I want to be very clear: I was senior author of this study and we're not saying to drop aspirin right away. These people got aspirin at the time of the procedure and for 3 months after. These were not STEMI patients. They had a high risk for bleeding and ischemic events. DAPT was continued for 3 months and then aspirin was dropped or continued. What we found is no surprise. If you drop aspirin, which inhibits prostaglandins and causes gastric erosion and bleeding, you get less bleeding. The important thing is that there was no excess risk for ischemic events.

Ischemic events were less frequent than we thought, but we did hit the noninferiority criteria for ischemia. The risk for death, MI, or stroke was 3.9% in both groups. The difference in all-cause death was 1% versus 1.3%. It was 2.7% for MI in both groups and there was no difference in stroke or stent thrombosis. I think this will change practice. You have to make an assessment about what is best for each patient individually, but for the high-risk bleeding, high-risk ischemic patients, this certainly moves the needle toward shortened duration of DAPT, say, for 3 months. The results really apply to ticagrelor, not to clopidogrel or prasugrel, so those would need to be evaluated independently.

Harrington: I too saw this as potentially practice-changing when I saw the results at TCT and then read the paper. We were all using things like the DAPT risk calculator—we were calculating bleeding risk and then trying to make an individualized decision, and that is quite appropriate. Here we have a nice piece of data that for high–bleeding risk, high–ischemic risk patients, you can drop the aspirin and just continue ticagrelor monotherapy. That is a step forward and will change practice as people become aware of these data.

This has been a fun discussion. Let's call an end to this section; we have more to come, so we hope people will listen to the next installment in 2020. My guest has been Mike Gibson from Harvard Medical School, Beth Israel Deaconess, and the Baim Institute. Mike, thanks for joining me on Medscape Cardiology for part 1 of the Best of Cardiology in 2019.

Gibson: Cardiology is back.

Bob Harrington, MD, is chair of medicine at Stanford University and current president of the American Heart Association. (The opinions expressed here are his and not those of the AHA.) 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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