Does PIONEER-HF Warrant Acute HF Indication for ARNI?

Interviewer: Ileana L. Piña, MD, MPH; Interviewee: Javed Butler, MD, MPH, MBA


December 13, 2018

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña from Albert Einstein College of Medicine and Montefiore Medical Center. This is my blog, and I have an opportunity here at the American Heart Association to have a lot of interesting discussions because the faculty here is fabulous. Some of them made great new presentations. I hope you heard our conversation with Eric Velazquez, who was the principal investigator of the PIONEER-HF trial.[1] The PIONEER-HF trial [evaluated] sacubitril/valsartan in a more acute setting [and was recently published] in the New England Journal of Medicine (NEJM). Javed Butler, a clinical trialist like me, is here to help discuss the findings.

Javed Butler, MD, MPH, MBA: Thank you very much. Great to be here.


Piña: Eric Velasquez gave us a wonderful interview about PIONEER-HF. Everywhere, I keep seeing these separated curves that show statistical significance [in the serious composite endpoint of death, rehospitalization for heart failure (HF), and left ventricular assist device (LVAD) or cardiac transplant] of what was not a [true] endpoint. It was an exploratory analysis. The death was even. What do you think about the comparison between the angiotensin receptor-neprilysin inhibitor (ARNI) and 10 mg of enalapril? They push for the higher dose, which I'm happy to hear because when it's being used in the community most people are at the low dose and maybe the medium dose (which was never tested in the trial). So they really did push for the higher dose. Well, 160 mg of valsartan twice daily is not 10 mg of enalapril.

Butler: It's 10 mg twice daily of enalapril.

Piña: It's not 10 mg twice daily, it's more like 20 mg. We see the N-terminal pro–B-type natriuretic peptide (NT-proBNP) take a dive down with the angiotensin-converting enzyme (ACE) inhibitors or the angiotensin II receptor blockers (ARBs) and spironolactone and diuretic. Are you impressed?

Butler: Let's take one step back and ask why this trial was done. This is really a fundamental question. All the HF drugs that are approved were on the basis of outpatient treatment. The issue that always comes up is whether you can use it in the inpatient setting. I would argue that you really don't need to test it in the inpatient setting because it's the same disease that has a decompensation event. To me, the bigger issue is safety. Is it safe to start in the person who is recently decompensated? I think that question was answered.

Piña: I agree. An ACE inhibitor or an ARB is safe to do in that respect.

Butler: There were a few holes in the PARADIGM-HF trial[2] that are not completely plugged. PARADIGM-HF had no patients with de novo HF. There were very few African American patients and here [in PIONEER] we have about 35% African American patients.

Piña: I see it as consistent. But the mortality did not change.

Butler: Let's come to that. Because the idea was to primarily prove that it is safe, this was a small study. It was an 800-patient study and they chose a biomarker as the primary endpoints. One can argue about that. Certainly, it was not powered to look at the long-term outcomes. Then the issue is the consistency. If you look at the primary [exploratory] composite endpoint, obviously there were negligible transplant and LVADs that we can just ignore those. Then it comes down to mortality and hospitalization. The overall number of mortality events was only 25 and there was a 32% reduction. The hazard ratio (HR) was 0.66.

Piña: It was a low-mortality population to start with.

Butler: Correct. The confidence interval is pretty wide, as you would expect. The point estimate showed a 33% reduction, which is sort of consistent with a bigger trial. Even with the small study, there were about 3 times more HF events. There were about 25 mortality events, about 100 HF events, and that reduction reached statistical significance. The HR was 0.56.

Whether it is kosher to combine the 33% mortality benefit with the 44% HF hospitalization benefit or whether we should look at it separately, we can all have that argument. That argument stems from whether you're going to label this drug as an acute HF drug or not.

Piña: There is my question.

I don't take it as an acute HF drug. I'm not going to start it in the emergency room.

An 'Acute Heart Failure Drug or Not'?

Butler: As far as I'm concerned, heart failure is heart failure is heart failure.

Piña: All the patients had been decongested before they got enrolled. In other words, you had already done the diuretic or whatever. For me, it would have been intravenous nitroglycerin and a diuretic. So you are already picking a population that is nearly ready to go home because after 4 days they are telling us to kick them out of the hospital.

Butler: We have never had a randomized controlled trial of a drug being initiated in a hospital that showed posthospitalization benefit. Also, remember that not only was it a small trial, it was 8 weeks. Very short.

Piña: But the proBNP went down pretty quickly and that is a learning piece. It does not take long to get the proBNP down. I see it in the clinic and it happens pretty quickly without remodeling having been proven. Remodeling may happen later but the proBNP is down, so I think those are learning and teaching points.

Butler: Absolutely. I don't take it as an "acute" HF drug. I'm not going to start it in the emergency room or something like that. That was not studied. We have a secondary analysis of the PARADIGM-HF[3] trial that shows a 38% risk reduction after the first hospitalization. Basically, it is a very good drug for chronic HF.

Piña: I agree it's a safety issue.

Butler: The practical part is that the biggest teachable moment is in the hospital. There are a lot of studies in multiple different diseases finding that the best chance for long-term adherence is if a drug is started in the hospital. We have that opportunity.

Piña: We learned this so well from the beta-blockers. I use ACE inhibitors and ARBs at that point.

Just to finish up, we had a wonderful session on shock. I was to talk about the pharmacologic care of shock, for which, of course, there are no randomized control trials. I made the point that every time we have an acute HF trial, nowhere in that protocol—because I've done them myself—does it tell you what to do after the 48 hours. I love these discussions.

Thank you for joining us today. I hope you read the paper in NEJM. The trial is called PIONEER-HF and Dr Velazquez is the first author. I think you will find it extremely interesting.


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