An Interview With PARADISE-MI PI Marc Pfeffer

Sacubitril/Valsartan: Trending Toward PARADISE Post MI?

Ileana L. Piña, MD, MPH; Marc A. Pfeffer, MD, PhD


May 19, 2021

This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello. This is Ileana Piña from Central Michigan University with a special blog, because we're coming to you during the American College of Cardiology 2021 scientific sessions. This meeting is completely virtual for the second year in a row.

Early on Saturday, we attended the first set of late-breaker trials, and the very first presenter is with me today: my good friend, Marc Pfeffer, from the Brigham and Women's Hospital and Harvard Medical School. Marc has been a leader in clinical trials for many, many moons. Marc, as usual you continue to present wonderful work. I'm having a déjà vu of the SAVE and VALIANT trials, and I imagine you feel the same. Tell us about the trial you presented today, PARADISE-MI.

Marc A. Pfeffer, MD, PhD: For 30 years, patients who have had a myocardial infarction (MI) have benefited from drugs that inhibit the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors reduce death and the development of heart failure. When angiotensin receptor blockers (ARBs) came out, there was a vigorous effort to see if these could do better than the ACE inhibitors, and they did. Valsartan was at least as good at preserving the benefit of the ACE inhibitors. Then we saw what happened with sacubitril/valsartan in heart failure, especially in the PARADIGM-HF study, where it was superior to enalapril in saving lives and reducing heart failure complications. I tried to get the sponsor of that study to let us test it post MI because it's a natural progression. If you can treat the symptomatic person, why not prevent the development of MI altogether? Eventually we got the resources and put a team together and studied it in PARADISE-MI.

Piña: More than a team. This was an international study.

Pfeffer: Our endpoint was death from cardiovascular (CV) causes and hospitalization for heart failure, which all the other studies have as endpoints. But we added outpatient development of heart failure because sacubitril/valsartan is already proven to be effective in people with heart failure, and we didn't want to deny them the benefit of the proven therapy. So, let's look at high-risk MI patients.

Piña: What did you consider high risk?

Pfeffer: High risk included anyone who comes in with a low ejection fraction (EF), 40% or lower, or signs and symptoms of transient pulmonary congestion. The Killip class also has always tracked with not doing well and with later development of heart failure. Patients with existing heart failure were excluded from the study. In all, 5661 patients were randomly assigned to either sacubitril/valsartan or ramipril, with no run-in of the doses; our average time to full dose was 4.2 days.

The composite primary endpoint (CV death, heart failure hospitalization, outpatient heart failure) was 10% lower with sacubitril/valsartan. We needed 15% to declare significance, so 10% was not significant. But you have to learn something from a clinical trial, and we did. We probed, and every analysis we conducted favored sacubitril/valsartan numerically. We didn't just look at the first event but the total burden of heart disease, and we looked at recurrent events. Then it became quite clear that you'd rather be on sacubitril/valsartan. The other issue was that the last 10 months of the trial were conducted during COVID. Participants weren't coming in, so we relied on the investigators regarding when their patients developed heart failure. When we looked at that, once again, we saw an important reduction with sacubitril/valsartan over ramipril.

Knowing what you do with heart failure, the safety profile is going to be very important because this is the first major trial [of sacubitril/valsartan] with no run-in. They were critically ill people; they signed consent; they got either sacubitril/valsartan or ramipril. And the safety profile was really balanced. The total number of people discontinuing therapy was similar in both arms; the total adverse drug events were similar in both arms but the pattern was a little different. You know this pattern very well: With sacubitril/valsartan vs an ACE inhibitor, you're more likely to have more hypotension, but you're less likely to have cough. But all the totals were the same. We concluded that sacubitril/valsartan was as safe as an ACE inhibitor. We couldn't declare effectiveness because it didn't reach significance, but every time we looked, we saw something there. So for you and the heart failure community, I believe this should be a barrier-removing study. Why wait until someone is really sick?

Piña: Thank you, Marc.

But first, do you think a lot of this is dosing equivalency? I've had this question with PARADIGM since the beginning, and I've challenged the principal investigator (PI), John McMurray, on this because I look at the dosing of the sacubitril/valsartan, and the valsartan content is 160 mg; that's for the valsartan alone. But that's equivalent to 20 mg of enalapril twice daily, not 10 mg, which is half-dose. I have often wondered whether the results are all dosing related. I'm glad you used ramipril because you already have data on ramipril from the AIRE and TRACE trials. We never did the prospective MI trial of enalapril; I believe in one of the large MI trials, lisinopril given early prevented remodeling 6 weeks post MI. So there's something about blocking the renin-angiotensin system early that is highly beneficial. I don't think people are administering it as they should, but it's highly beneficial. Is it all sacubitril or is the dosing very different?

Pfeffer: Scott Solomon and I were doing a study with echocardiograms post MI to see when was the best time to start ACE inhibitors. And the GISSI and ISIS people, among others, did a meta-analysis and found that within 1 day there was a benefit of an ACE inhibitor. So we stopped our trial, because why play around with an echo when the drug is already saving lives with early and sustained use? So the best benefit is when you start early and sustain it. Regarding the dose, I'm so glad you mentioned John McMurray because there's nobody better in the world who can tell you about dose equivalents. He did CHARM-Added, as you know, and was the expert on dose equivalents. I give them credit in PARADIGM for testing against enalapril, one of the best drugs for heart failure, and proving that the enalapril dose was the dose used in the studies. We did the same with ramipril in PARADISE; our dose is what was used in AIRE. That has nothing to do with your question about the sacubitril/valsartan dose, but at least we're going against proven drugs at proven doses.

Now the combination. In VALIANT, we hardly ever talk about it but we combined an ACE inhibitor and an ARB. Because of that we could definitely say that if you really blocked this system, you didn't get any more benefit but you got more adverse events. That's why sacubitril is a different add-on than just more of the dose. And that's why I think PARADIGM was very effective and why we just used their dose.

Piña: Sacubitril/valsartan is much more expensive than ramipril, and certainly much more expensive than enalapril. If it's on the hospital formulary then it's easy, because you can just give it, but if it's not, then you have to jump through some hoops. Many insurers aren't paying for it. It would make sense to me to start with ramipril in the hospital and then switch the patient over to sacubitril/valsartan as an outpatient. Maybe you would even prevent some of that hypotension — this is just me thinking.

Pfeffer: People don't do that, because when you're in the midst of an MI, that's the therapy. If you don't start a statin then, it's not happening. And by the way, about 90% of patients in PARADISE were started on statins.

Piña: The background therapy was great. I noticed that a lot of the patients were on spironolactone, which was also very good to see, in accordance with the EPHESUS trial. I found your last slide particularly fascinating.


For our audience who don't remember, Dr Pfeffer was the PI of the SAVE trial, which is the most beautiful example of going from the laboratory to the bedside. And you did this with your wife, Janice.

Pfeffer: It was a rat study. But we took it all the way to the concept of remodeling and the concept of ACE inhibitors. New doctors don't know that we weren't born thinking "remodeling."

Piña: That's why I'm talking about it, because our audience is extensive and our viewers are of different positions, age, and time in practice. I want them to realize how we have moved the field. When you show that graph of the ACE inhibitor and the ARB in the 1990s and early 2000s, we had a much higher mortality rate than we have now.

Pfeffer: I love using mortality when I want to compare two trials, because you might define CV events and you might define heart failure differently, but you can't define death differently.

Piña: As cardiology pioneer Jay Cohn says, death is death.

Pfeffer: Back then, mortality rate was 30% at 3 years with placebo. The ACE brought that down to about 25% and the ARBs are about the same. But where we are today, at around 10% mortality, is not because of just one thing; it's because of many things. That's why I took a minute to compliment the audience.

Remember thrombolytics. We were injecting a lytic agent into your veins. Wait a minute, that's good, but what about opening the artery? Then, what about opening it with a coated stent, and what about opening it with a coated stent and dual antiplatelet agents, and then at 90 minutes door-to-balloon.

It's one thing for the trialists to say that; it's another thing for the community to do it. So let's give the cardiovascular community a round of applause. They're doing it. And now we're trying to be better than good. That's the goal — to be better.

Piña: We should also congratulate EMS because it means that with projects like the American Heart Association's Lifeline, the patients are coming in quicker. Certain hospital systems are able to deal with this on a 24-hour basis, so the patients don't go to one place and then have to be transferred. To me, that slide shows a triumph of taking what we learned, putting it into practice, and then looking at it again. You didn't use the words, but would you call PARADISE a superiority or a noninferiority trial?

Pfeffer: It has to be a superiority trial. What's the advantage if we were only as good as? You have to get to better than. I just got a note from former FDA Commissioner Rob Califf, who has always been concerned with performance measures. I remember him saying, "When you buy french fries and a hamburger at McDonald's, there's always a ketchup pack in the bag. That's because someone gave them feedback." That's what has happened in cardiovascular medicine. Hospitals are getting report cards — how many patients leave your CCU with instructions — and it worked. That's what that last slide shows: It's worked.

Piña: I was proud to see that. I want to thank you, as usual. Your presentations are elegant, and this was a tough trial to complete because you ran it during the pandemic. And it was international, so you had some countries that were severely affected by the pandemic, and yet you accomplished this.

Pfeffer: Some investigators got sick. We had a site in Hunan province. Who would have known?

Piña: Thank you for your time today. And thanks to my audience for watching. This is Ileana Piña. Stay tuned for more from the ACC.

Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA's Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.

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