TRUE-AHF: Better to Prevent vs Treat Acute Decompensation

An Interview With Dr Milton Packer

Ileana L. Piña, MD, MPH; Milton Packer, MD


December 02, 2016

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Ileana L. Piña, MD, MPH: Hello. I am Ileana Piña, from Montefiore Medical Center and the Albert Einstein College of Medicine in New York. This is a piece of my blog. I am thrilled to be here at the American Heart Association national meeting —we call it "sessions" —where we always look forward to hearing the science, whatever is new and whatever we have planned, and the trials that we have done, and now finally getting some of the results.

I am fortunate today to have my good friend, Dr Milton Packer, who has been, as many of you know, always on the forefront of what we need to know in heart failure. He has really been dedicated to getting the right answers and doing the right trials. Milton, welcome.

Milton Packer, MD: Thank you very much. Good to be here.

Dr Piña: The theme of acute heart failure is something that I have discussed with the audience here, but we do not have the next best drug for this. You have been thinking about this for a long time. Tell us about the hypotheses of acute heart failure.

Acute HF Like ACS?

Dr Packer: It is really interesting, because everyone realizes that acute heart failure is a congested state. There is an increase in intravascular volume. There is cardiac distention. There are worsening symptoms.

Dr Piña: The pressures are going up.

Dr Milton: Pressures going up. Wall stress goes up. Everyone has recognized that. There is another pathway in acute heart failure, which is that people with acute heart failure also have evidence of cardiac microinjury. They spill troponins after an episode of acute heart failure. They have increased risk for hospitalization, increased risk for cardiovascular death. One almost gets the impression that the cardiac distention is the cause of cardiac microinjury. It makes acute heart failure start to feel like an acute coronary syndrome.

Dr Piña: Exactly. A lot of parallels between the two.

Dr Milton: In fact, so many parallels have been drawn that there are a number of individuals, including guideline writers, who have said that time is of the essence in acute heart failure.

Dr Piña: Get to them quickly.

Dr Packer: Get to them quickly, decompress the heart, decongest the intravascular space. If you can do that, you will save myocardia.

Dr Piña: Get rid of the volume.

Dr Packer: Get rid of volume, make the heart smaller. If you make the heart smaller, you will save myocardial tissue.

Dr Piña: That has been the theory.

Dr Packer: We just wanted to know whether that theory was right. We had an opportunity to study a drug, ularitide. Ularitide is a natriuretic peptide, natural occurring, usually made by the kidney—as opposed to a BNP [B-type natriuretic peptide] which is made by the heart (lots of organs have their own natriuretic system). We thought that it would be appropriate, given the willingness of the sponsor to evaluate the drug to test this hypothesis in a clinical trial. TRUE-AHF is not your typical acute heart failure trial for a couple of reasons. First, we wanted to make the intervention as rapidly as possible.

Dr Piña: One of the criticisms in the past has been that we waited too long to give the intervention and that is why it failed.

Dr Packer: Exactly. A major effort was made to have the shortest time to intervention possible, and in fact, it was only 6 hours in this trial.

Dr Piña: Which is amazing, because the patients sometimes linger in the ED before we even get called; it takes a huge effort.

Dr Packer: The second thing that we did that was unusual, and up to now has not been done, is that we actually designed, sized, and powered the trial for cardiovascular mortality. Other trials have reported cardiovascular mortality based on a relatively small number of events.

Dr Piña: As an afterthought—almost a secondary tertiary endpoint.

Dr Packer: We said that we can actually study this in a definitive manner. We also did one other thing that was really interesting: We prospectively identified and adjudicated in-hospital worsening events. No one has ever done that before.

Dr Piña: There is a lot of talk that worsening heart failure while you are in the hospital has a greater predictive value than what you did when you came in.

Dr Packer: We made that a particular focus.

No Long-term Benefit

Dr Piña: What did you find?

Dr Packer: We found that ularitide did exactly what we expected it to do. Its vasodilator effects resulted in a lowering of blood pressure, and N-terminal pro-BNP dropped almost 50%. There were signs of intravascular decongestion; hematocrit rose.

Dr Piña: Everything in the right direction.

Dr Packer: Everything went in the right direction. Not only that, but there was a major reduction in in-hospital worsening events. Adjudicated in-hospital worsening heart failure was very striking while the drug was given.

Dr Piña: How long was the infusion?

Dr Packer: The infusion was 48 hours. The effects had disappeared about 6-12 hours after the infusion was stopped. What we thought was most interesting was that it is only working for 48 hours, but maybe it is a critical 48 hours.

Dr Piña: That is what we have all thought.

Dr Packer: That is what we hoped. But there was no effect on cardiac troponins. No effect on rehospitalizations.

Dr Piña: Really? No effect on troponins?

Dr Packer: No effect on cardiovascular mortality. The drug worked when we gave it. It stopped working when we stopped the drug.

Dr Piña: Sounds very logical.

Dr Packer: I think we have led ourselves to believe that maybe something magical that we do in an unbelievably short period of time is going to change a disorder that actually started days and weeks or months beforehand.

Dr Piña: As we know, the pressures are rising way before anything else goes on.

Dr Packer: To think that we can give a drug for 48 hours and that it is going to change the natural history of the disease for months and years afterwards—I am sorry; that is not true.

Use What Works to Avoid Hospitalization

Dr Piña: Did the study protocol tell the investigators, "When you are done with the infusion, go back to the evidence-based care that we know does work"?

Dr Packer: It was mandated, and both the placebo and ularitide-treated groups got what was considered guideline-directed therapy.

Dr Piña: I hope you are going to publish that—what happens immediately after—because I have always said that although I am trying to decongest the patient with a diuretic, a nitrate, I am also uptitrating the good drugs.

Dr Packer: The thing that is so important about the "good drugs"—I like that phrase—is that people with heart failure take them 95% of the time. The whole goal is not to go into the hospital in the first place, and if we go into the hospital, the goal is to get them on these good drugs as soon as possible and get them home as an outpatient. All of this incredible attention to what happens with this intervention in a small time period—it's a bit too little too late.

Dr Piña: That is fascinating. What do you think will come next in this field of acute heart failure?

Dr Packer: I hope some wisdom.

Dr Piña: We have not had enough of that.

Dr Packer: I hope that physicians will understand that the best way to treat hospitalization for heart failure is to prevent it from happening. It is really not that complicated.

Dr Piña: It does require you to see the patients more frequently. You have to use patience to get them up to their doses, and you have to continue educating them at every turn.

Dr Packer: The fact is that when we look at what happens in the real world, most patients with heart failure are not getting the best drugs at the best doses to prevent hospitalization. It is just not happening.

Dr Piña: They are not medicated properly. I agree. We have done so many trials, and now we have so many good things that we can offer the patients.

Dr Packer: We can, and it is amazing. We should use them. If we use them, we would make trials like TRUE-AHF totally obsolete.

Dr Piña: I often will say to the patients when they call us, "If you are having problems between 8 AM and 5 PM, do not go to the ED; call us. I can see them in the office, and sometimes with a little nitro paste, they can feel better; give them a shot of diuretic; see them the next day. What you do in the hospital the whole time is try to diurese them. That is what you are doing for 48 hours.

Dr Packer: Physicians have been preventing hospitalizations for heart failure for years. The goal is not to do something magical when they're in the hospital; the goal is to not put them in the hospital at all.

Dr Piña: Keep them out of the hospital. This is fascinating. I want to thank you for your vision. I think we answered an important question. It was always that we have not been doing this quickly enough, that we need to do it faster. Six hours really is an amazing feat.

Dr Packer: It is.

Dr Piña: Back when we did the OPTIME-CHF study,[2] it was more like 14 hours before we got to the patients, and we always said we've missed the window. Now we know that the window maybe does not exist.

Dr Packer: It does not exist.

Dr Piña: Thank you again for coming today.

Dr Packer: I am delighted.

Dr Piña: Thank you for joining me today. This is Ileana Piña, signing off. Have a great day.


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