COMMENTARY

PIONEER: A Role for ARNI in Stabilized Acute HF?

Interviewer: Ileana L. Piña, MD, MPH; Interviewee: Eric J. Velazquez, MD

Disclosures

November 29, 2018

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña, from the Albert Einstein College of Medicine in New York and Montefiore Medical Center. We are here at the American Heart Association [Scientific Sessions].

I'm very lucky today to have with me Dr Eric Velazquez, who is a great colleague, a good friend, and who recently became chief of cardiology at Yale. Today he presented PIONEER.[1] Eric, thank you for joining us. I was there when Eugene Braunwald got all of us together because he wanted to do this study—and you guys did it. Please tell us a little bit about the trial and the background.

Eric J. Velazquez, MD: Sure. The background, simply put, is that acute heart failure hospitalization is the number-one reason for hospitalization in the United States among the Medicare population. And acute decompensated heart failure has really not changed dramatically in terms of its care. The standards of care remain decongestion with diuretics and vasodilators for hemodynamic stabilization. We really don't have guideline-directed therapy for that population of acute decompensated heart failure. That was really our background.

And then we had information that came from PARADIGM.[2] Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI) compared with enalapril, the angiotensin-converting enzyme (ACE) inhibitor, led to a reduction in cardiovascular deaths and heart failure hospitalizations. And that was a paradigm-changing program, but they did certain things with their design that left some questions unanswered. We wanted to tackle those questions. They had excluded patients with acute decompensated heart failure.

Piña: So it was meant to be a chronic heart failure trial?

Velazquez: It was a chronic trial, and they required patients to be on stable heart failure therapy before they were enrolled in the sequential, single-blind, run-in phases with the highest doses of the drugs. And then they were randomized, so we didn't have a lot of information on de novo heart failure patients in the acute setting—patients who were unable to tolerate the high doses and patients who had not previously been on renin-angiotensin system (RAS) blockade. So that was a lot of questions that we felt we could add to PARADIGM to allow further information that might impact the care of patients.

Piña: Did you have an idea of how many days into the hospitalization you would start the trial? Is it toward the end? Is it early?

Velazquez: We wanted to start the trial as soon as patients were stable. We required at least a 24-hour window of hemodynamic stabilization from the time they presented to the emergency room, and then they could be enrolled through 10 days of hospitalization. And we wanted to define—which is not done consistently—what a hemodynamically stable patient would be in whom we would want to start this drug.

Piña: Did you define it?

Velazquez: Yes. We used maintenance of a systolic blood pressure of 100 mm Hg or greater and no need for intensification of intravenous (IV) diuretics or use of IV vasodilators in a 6-hour window before they could be randomized.

Piña: So they could still get IV diuretics because they usually keep getting them, but within a window?

Velazquez: They just didn't have to have it intensified in the last 6 hours. They weren't allowed to have had IV inotropes within the previous 24 hours. That was our definition, right or wrong, of hemodynamic stabilization.

Piña: That's all right as long as you define it and carry it through.

Velazquez: Then we randomized patients 1:1—440 patients were randomized to sacubitril/valsartan and 441 to enalapril.

Piña: And what was the dose of the ARNI?

Velazquez: We started dosing using a systolic blood pressure titration algorithm that was the lowest dose. It was based on blood pressure, so if your blood pressure was between 100 and 120 mm Hg, you were randomized to 24 mg of sacubitril with 26 mg of valsartan, or enalapril 2.5 mg twice daily.

And then based on blood pressure thresholds that changed through the trial—we had a 1-week threshold that had to be met and then biweekly after that—we allowed uptitration to the target dose, which was the 97/103 mg sacubitril/valsartan versus 10 mg twice-daily (BID) enalapril.

Piña: Which is 160 mg BID valsartan, essentially.

Velazquez: Yes. Enalapril 10 mg BID was the target dose. We saw that about 60% of the population, by 8 weeks, using that titration algorithm, got to the target dose of enalapril and about 55% got to the sacubitril/valsartan target dose.

We had three basic aims of the program. One was to evaluate safety, which was an important secondary endpoint. Our primary endpoint was a biomarker, which I think is well recognized as a clinical surrogate of efficacy, which was NT-proBNP. We looked to see if there was a change in the percent change from baseline to the mean of weeks 4 and 8.

Piña: So, what was baseline NT-proBNP? Was it the day they got randomized or was it the day they came into the hospital?

Velazquez: It was the day they were randomized. The screening NT-proBNP, which could have occurred any time before randomization and was required for enrollment, had to be over 1600 pg/mL.

Piña: That's not very high, 1600 pg/mL, in hospitalized patients.

Velazquez: Well, to get in; but the median that we actually achieved in the screening population was 4800 pg/mL.

Piña: So that's screening before randomization.

Velazquez: At randomization, it was a blinded assessment of NT-proBNP. And we now know and we reported that it was roughly in the 2500-2800 pg/mL...

Piña: So in other words, they got treated. Obviously, the diuretics—everything lowers the NT-proBNP.

Velazquez: Yes, they were decongested. The median time to randomization was 68 hours, and 25% were randomized within the first 48 hours. It was a stabilized acute heart failure population.

I mentioned NT-proBNP as our primary efficacy endpoint. We looked at four major safety events: symptomatic hypertension, worsening renal function, angioedema events, and hyperkalemia. And then we looked at several exploratory clinical outcomes. We identified a serious clinical composite of deaths, rehospitalization for heart failure, implantation of a left ventricular assist device (LVAD), or listing for transplantation.

Piña: All of the outcomes that you know can happen.

Velazquez: And then we also looked at other exploratory outcomes, including how often medication changed post-discharge. We showed that enalapril, in that 8-week period from baseline to the mean of weeks 4 and 8, was associated with a 25% reduction in NT-proBNP, and sacubitril/valsartan was associated with a 47% reduction. There was a 29% relative risk reduction of NT-proBNP lowering in favor of sacubitril/valsartan, which was highly statistically significant.

In regard to the safety endpoints, we were glad to see that there were absolutely no statistically significant differences between the two study arms, even in renal function. And that was consistent. I think it was very nice to see and it was reassuring. What was really exciting was that in our exploratory clinical outcome of serious clinical composite, we had a rate in the enalapril arm of approximately 16% and a rate in the sacubitril/valsartan arm of about 9%. That was an absolute risk reduction of 7.5% at 8 weeks, which is pretty impressive. That was associated with a relative risk reduction of 46% in favor of sacubitril/valsartan, which was statistically significant.

Then we started looking at 12 subgroups, which were of clinical interest. There were some that I'll mention in a moment, which we identified a priori as very important to us. The good news is that regardless of whether you looked at the primary efficacy endpoint, the serious composite, or even the safety events, there was no statistical heterogeneity. In every subgroup, everything favored in the same direction. When we looked at patients, 36% of the enrolled population self-identified as black.

Piña: We really needed data on African Americans.

Velazquez: There was no heterogeneity in the effect in that group. We looked at women; no heterogeneity in the effect.

Piña: What happened to mortality?

Velazquez: For mortality, there was a difference. There were 15 events in the enalapril arm and 10 events in sacubitril/valsartan arm. The composite was driven by a 44% reduction in heart failure hospitalizations.

Piña: Wouldn't you think that anything that reduces hospitalization should also reduce mortality since we know that the two are correlated? But sometimes when you fix one, you didn't fix the other one.

Velazquez: I think what you want to see is for them to do both. And I think that's reassuring, particularly if it's a small trial like this. The other subgroups, which I'll just mention—a third of patients were de novo heart failure. This hospitalization was their index diagnosis—their first diagnosis ever. Two thirds were acute and chronic; no difference in the effects. The point estimates were aligned, which is very reassuring. When you look at the patients, because of the de novo heart failure population, 52% were not on an ACE inhibitor or an angiotensin receptor blocker (ARB).

We can talk about that another day. But we knew this was going to be the case. The CHAMP registry[3] and other registries have shown us that.

Piña: Actually, I think in the United States, we're starting to see a decrement in the use of RAS inhibition. I see that in our place, right or wrong.

Velazquez: The good news was that, again, the point estimates for people on or off ACE inhibitor or ARB were the same; they were consistent. The safety points we mentioned were consistent across all segments.

One comment about the angioedema events, because it wasn't statistically different between the groups but I think it bears mention, was that there was one event in the sacubitril/valsartan arm in a white patient and six events in the enalapril arm, all in black patients. So we're going to have to investigate that a little bit more because of small numbers.

Piña: We know that, in the literature, African Americans have a much greater propensity for angioedema.

Velazquez: That actually surprised us. I think we went into it with some concern that sacubitril/valsartan might cause an increase in angioedema events. But we've actually been showing something different.

Piña: The omapatrilat story didn't repeat itself.

Velazquez: We went after a population that had not been well studied, for which we don't have clear guideline decisions around therapy beyond decongestion and IV vasodilators for hemodynamic stabilization.

Piña: Most of our acute trials of vasodilators, even nesiritide—when you were at Duke that you led—doesn't tell you what to do after the first 48 hours.[4] It's just not been addressed.

Velazquez: In putting it all together, we had an 8-week trial. We were able to do an 8-week trial because we felt that the population that we put in PIONEER at 8 weeks was more and more like a PARADIGM patient. So we didn't feel that we had to continue with long-term.

Putting the total package together of the PIONEER and the PARADIGM study, the implications are that we believe we have data now to suggest that in-hospital initiation of sacubitril/valsartan is safe, is effective in terms of surrogates, and showed a very nice signal of efficacy clinically. We suspect that this will be emerging as a potential standard.

Piña: At the end of the trial, were patients left on sacubitril/valsartan?

Velazquez: We did not present that this morning or in our New England Journal paper. Because we wanted to preserve the blinding, all patients were, in a blinded fashion, transitioned to sacubitril/valsartan. We are now in the midst of evaluating that data to see what happened between 4 and 12 weeks because, as you know, there is a need to wash out an ACE inhibitor. We didn't want to unblind everyone, so we decided to build in those months of open label of sacubitril/valsartan. It's also safe.

Piña: It's also safe. Congratulations on your presentation. I'm proud to say that I was there the day that everybody thought of this.

For our audience, the New England Journal paper appeared today; Eric Velazquez is the first author. I think we're adding to the knowledge base that we really need.

Thank you, Eric, for joining us today, and I hope we'll bring you back when you find out what happened to those patients toward the end of the 12 weeks.

This is Ileana Piña. I'm signing off from the American Heart Association in Chicago. Have a great day, and thank you for joining me.

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