Quick, Reliable Marker to PUSH Decongestive Therapy in AHF

Recorded August 28, 2023. This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello! I'm Ileana Piña, professor of medicine at Thomas Jefferson University, and a heart failure transplant cardiologist. I am here at the European Society of Cardiology.

There's been a large amount of talk at this meeting about diuretics — those wonderful drugs that none of us really know how to give, how to use, how to recommend — and when anybody wants the standard of care, it depends upon what hospital you're in and what city you're in. We need to decongest patients. There's no doubt about it.

Now, with the sodium-glucose cotransporter 2 (SGLT2) data, there are still discussions about whether that's a diuretic and what to do with the loop diuretics when you put the patient on the SGLT2? It doesn't matter whether it's empagliflozin or dapagliflozin; it's basically the same.

This is a very interesting trial that we're going to talk about, and I have my good friend here, Wilfried Mullens from Belgium, who will be a discussant in this trial. The trial was called PUSH-AHF. Tell me about this PUSH concept of natriuresis.

PUSH-AHF

Wilfried Mullens, MD, PhD: The trial was designed based on a consensus document that we wrote within the European Heart Failure Association a couple of years ago, trying to help physicians guide diuretic therapy better. We suggested at that moment in time, with a group of self-proclaimed experts, that we should guide diuretic therapy not so much based on diuresis only but also on natriuresis — so on the quality of the urine. We suggested that if you don't reach a spot urine sodium content threshold of 70 mEq/L, you should escalate and increase the dosages of loop-diuretic therapy.

Piña: If 70 isn't enough, what would be acceptable?

Mullens: Acceptable would be everything > 70 mEq/L. Everything below would mean escalation of therapy.

Last year, we presented the ADVOR trial, where we actually combined loop-diuretic therapy with acetazolamide, showing a tremendous benefit on decongestion rates. Jozine M. ter Maaten, from Groningen, now took it one step further, and she was trying to validate this natriuresis-based approach.

There has been one trial so far, which is called the ENACT-HF trial, recently presented at the Heart Failure Association (of the ESC) meeting in Prague, that's already showed that, if you use that approach, you can increase natriuresis. The PUSH-AHF trial was looking at patients with acute heart failure with congestion and comparing a standard-of-care diuretic regimen vs that natriuresis-guided approach.

Piña: What did you call the standard of care in this trial?

Mullens: The standard of care was very smart because they didn't want to have people saying you underdosed.

Piña: Right.

Mullens: They looked at patients, and they looked at the glomerular filtration rate (GFR) and if they were diuretic naive. If the GFR was low and they were already on a diuretic, they had a really high starting dose to avoid criticism that the standard of care would have dosages that were too low.

Piña: That's very interesting.

Diuretic Escalation Protocol

Mullens: The intervention arm started at the same amount of loop diuretic. After 2 hours, physicians on the team needed to look at the natriuresis. If they didn't reach the threshold of 70 mEq/L, they had to escalate the dose.

Piña: There was a 2-hour minimum before you do the escalation.

Mullens: Exactly. It was at 2 hours, 6 hours, 12 hours, 18 hours, and 24 hours.

Piña: Now, who picked the actual diuretic? Did the investigator pick whatever was on their formulary?

Mullens: It was protocolized. It was a single center. It was furosemide in both groups. If they didn't reach the threshold, they had to double the amount of furosemide. If they reached a certain level of furosemide, they had to add a second-line agent, which was a thiazide most of the time, or acetazolamide.

Piña: Like the DOSE trial, where we used the hydrochlorothiazide?

Mullens: Exactly.

Piña: That's very interesting. What level of dose did the furosemide start at? What was the basic dose?

Mullens: The basic dose at home was about 2 mg.(Editor’s note: the median starting dose in both groups was 2 [1-4] mg of bumetanide twice daily; furosemide equivalent dose of 80 [40-160] mg.) They found that after 24 hours, when they had the primary endpoint, in the standard of care, patients received about 6 mg of bumetanide; in the intervention arm, it was 12 mg. That is really remarkable because almost half of the patients were diuretic naive. We always think that, if you're diuretic naive, it's going to work.

Piña: It's going to work.

Mullens: Even those patients needed escalation more than 80% of the time.

Piña: Amazing.

Mullens: Although they were receiving high doses with the standard of care, they still needed escalation of therapy. You have to individualize your diuretic approach.

Piña: Getting that sodium back quickly, you have to have a hospital who's willing to do that in the laboratory. I don't think any of us can get the sodium back that quickly, especially urinary sodium.

Mullens: I agree. If you look at their results, their primary endpoint was basically looking at if the natriuresis was better after 24 hours. It was definitely better.

Piña: Really?

Mullens: They hit the statistical significance.

Piña: The endpoint was just the sodium concentration?

Mullens: It was a coprimary endpoint. One of them was natriuresis after 24 hours, and they had a 20% increase in natriuresis by just using that algorithm. The other coprimary endpoint was heart failure hospitalization and all-cause mortality after 3 months. They didn't hit that one, but they were completely underpowered to do so.

Piña: It doesn't sound like many patients. How many patients?

Mullens: There were 310 patients from a single center.

Piña: That's still a small number.

Mullens: It's small.

Piña: That's pretty good for a diuretic trial.

Mullens: In ADVOR, we had 520, so this is almost the second-largest diuretic trial ever being performed.

Shorter Length of Stay?

Piña: In the United States, they want us to get the patients out more quickly. Do you think the length of stay was cut down because of the protocolized system?

Mullens: Their average length of stay was considerably shorter than what has been reported in other European countries. Remember, this was in Groningen, which is a top-notch heart failure center in Europe. The standard-of-care group, after the initial randomization phase, received really top care.

We showed, for example, in ADVOR, by just adding acetazolamide, you could reduce length of stay by at least 1 day. They didn't show that in this trial, but I think we have to take into consideration the limitations of the single, high-volume center.

Piña: Right now, we look at readmission rates, but the hospital system wants us to get the patients out sooner because they're paying more for that 1 extra day.

Mullens: That's different in Europe.

Piña: It is costly.

Mullens: If you look at ADVOR, the rehospitalization rate at 3 months was only 15%. It's more or less the same here in this PUSH-AHF population. You have to consider that in Europe, in decent trial settings, our hospitalization rates are considerably lower than what has been presented in the US. The rate of 15% — although it's still high, I admit that — is probably something that we have to accept in the patient population we're getting.

Patients in ADVOR were 78 years of age on average. In PUSH-AHF, they were aged 75 years on average; two thirds have chronic kidney disease, and most of them were on loop-diuretic therapy. They were really sick.

Piña: That did mirror the population.

Mullens: If you can reduce hospitalizations to 15%, that's not such a large number anymore compared with those, where it was almost 50% at 2 months.

Piña: Are they going to analyze all the other drugs the patients were on? In other words, did they get the SGLT2 inhibitors early?

Mullens: I don't know, but I think so. The beauty of this trial was they've done everything through the electronic medical record including the randomization and the data collection. Everything will be in there.

Piña: It's called a practical trial.

Mullens: It's really a pragmatic trial done via the electronic medical record system. I think that was beautiful. If you can design a trial — Jozine was still a fellow, a fellow published in Nature Medicine — then do it really pragmatically through the electronic medical record, that's fantastic.

Piña: That is and also much less expensive.

Mullens: Absolutely.

Piña: Who funded this?

Mullens: It was a Dutch network that funded it. I think they only got funding for the PhD student. There basically was no funding for the trial. They designed it because they're really good investigators. They're willing to find out difficult answers to difficult questions.

Piña: These are questions that most of industry will never ask.

Mullens: No, and they're very relevant.

Piña: They are so relevant.

Mullens: The conclusion, Ileana, is now, we have two trials, ENACT and PUSH-AHF, that unequivocally and consistently show that you can use an easily obtainable, cheap, reliable marker that can help you and I and everybody in the world to guide decongestive therapy.

I admit, we will not do that, but you have to incorporate it into your disease management program and your nursing staff.

Piña: I will try to do that the next time I'm on the inpatient service. Right now, I'm mostly in the clinic. In December, I'm going to be on the inpatient service. I'm going to try that.

Mullens: Good.

Piña: I'll contact you and let you know. Are you going to start doing it?

Mullens: Yes, we're already doing it.

Piña: You're already doing it?

Mullens: We wrote the paper a couple of years ago. We're already doing that.

Piña: Well, this is fascinating.

Mullens: It's less difficult than is perceived. People say it's too difficult, but if you give this to the nurse, it's just like measuring a blood pressure.

Piña: You order the lab test.

Mullens: It's a standard of care.

Piña: I think the most important is to get the lab to send it back to you fairly quickly.

Mullens: It's only one urine sample. You send it to the lab. It goes automatically. It comes back after half an hour. The nurse looks at the results.

Piña: It may not come back after half an hour for us. That's why we have to have a conversation with the lab and ask them to help us.

Mullens: Exactly, it's just the urine. It's like measuring a blood gas analysis and you have it immediately back.

Piña: I know.

Mullens: We have to change the mindset.

Piña: That's what we need to do.

Mullens: The authority should not only be in the hands of the physician, but we should give it to the nurses to do what they need to be doing.

Piña: Yes, and the pharmacists. That's right. This has been a fascinating discussion. Thank you. As a discussant, you know a lot about this trial.

I want to thank our audience. I hope that these little pearls that we give you will help you with your care of your own patients at your own institution. We're always talking about things that are doable and not too large, but small changes that you can make that may make a big difference to your population.

Thank you for joining me today. This is Ileana Piña signing off.

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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