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Dr Van Spall:
- I'm Harriette Van Spall, Associate Professor of Medicine and Cardiologist for McMaster University. I'm delighted to have with me Professor Alexandre Mebazaa, who is Professor of Medicine in University of Paris, Director of the INSERM Unit, and Chair of the Department of Anaesthesia and Critical Care in Paris. We are here at AHA 2022 to discuss his fabulous, STRONG-HF late-breaking clinical trial. Welcome, Professor Mebazaa.

Prof Mebazaa:
- Thank you, Harriette, for this invitation.

Dr Van Spall:
- I'm so excited about your trial because we have struggled with the implementation of evidence-based medical therapies for our patients with heart failure. Across jurisdictions, these lifesaving therapies are underutilised for a variety of reasons.
You led an implementation trial that tested a novel strategy to optimise therapies. Tell us about your intervention and how you were inspired to devise it.

Prof Mebazaa:
The initial idea was rather simple: I thought, "Why for chemotherapy if you have someone going to see her oncologist, and they discover that they have a cancer." Usually the oncologist will say, "Next Wednesday you come, we give you a full therapy and here is a small cart. If you have any infection or fever or whatever, you just call and you come, and we take care of you." Why can oncologists succeed to have this?
We have the right therapies for heart failure. We know the dose that we should give to heart failure patients, but we are not giving it just because there is this people or paper or textbook saying that it's maybe unsafe or there is a safety issue giving those drugs. Then, I thought, "Okay, let's do exactly like in case of a cancer and let's give the full therapy immediately, and then we take care of the safety issue." The idea was to give this treatment after acute heart failure.
Why after an acute heart failure episode? My group published many papers showing that regardless of the country, regardless of the continent, there is always the same story when patient is discharged from an acute heart failure episode: First, the chronic heart failure medications implementation is very low. We know that the readmission rate is very high. We recently published a paper, with 15.5 million acute heart failure over the last 30 years, the readmission rate is exactly the same today as in 1980: around 50% over one year. The number of deaths slightly improved over years, but we are still around 10 to 20% mortality rate in the year following acute heart failure. Then I thought, "Okay, here, after an acute heart failure episode where the number of events is very high, we need to do something." And the something is to implement the drugs as quickly as possible.

Dr Van Spall:
- Tell us about your intervention.

Prof Mebazaa:
- The intervention is rather easy to understand. The patient has an acute heart failure. In the first hours and days, he's still dyspneic and we give them oxygen and diuretics to try to decongest. After few days the patient is stable hemodynamically.
There is an opportunity, before he's discharged, an opportunity to start the implementation of heart failure therapies.
How are we going to do it? We first looked on patients who are really congestive. Then we took BNP level that was still high just before being discharged and patients who are still having a lot of fluids in their body. And then we decided for this intensive arm, to give half of the dose of beta blocker, ACE inhibitor, and spironolactone before being discharged.
After that we had following visits every week. At week one we test the half doses given before discharge were well taken by the patients and there is no safety issue. We are measuring several parameters.
The important step is week two. Exactly two weeks after being discharged, the physicians have to increase the three medications to full dose. 100% of the dose that is recommended by guidelines: Beta blocker, ACE inhibitor, and spironolactone. The patient will come in one week after this big increase of the medications and this will be week three. We will be also seeing the patient at week six and at 90 days.
In the usual care arm, we were doing exactly the usual local practise. We were writing a report on the patient when they were discharged, after this, the patient was sent to the physician or cardiologist in their town, to their own cardiologist who usually takes care of them. we were seeing this patient at 90 days.
For the two arms, between 90 days and 180 days, no special visits. And the primary endpoint was at 180 days. And to summarise, several visits, three, four visits after discharge. And at week two, the patients should be at maximum full dose for beta blocker, ACE inhibitor, and spironolactone. And during these visits, and this is very important, is usually even in my practise and in many people's practise, during the visit we did not know exactly what to do. And here we had a full procedure.
You should first do a biological exam, potassium, creatinine, natriuretic peptide, NT-proBNP, haemoglobin, the patient was doing this early morning. And then when the exam comes, the patient has the visits where clinical exams, we look at heart rate, blood pressure, whether there is edoema. We see the results of the biological exams. And then if it is week two, we increase the medications to full dose. Then we have two things, or three things even, we have when should we increase the medication, the pace of the visits, and what the visits should consist of?


Dr Van Spall:
- Fantastic, and who are the clinicians providing care in the intervention group?

Prof Mebazaa:
- In the intervention group, there are only cardiologists and mostly heart failure specialists. And we took centres where we have heart failure clinics and those are cardiologists who are usually taking care of heart failure patients.

Dr Van Spall:
- Fantastic. Tell us about your baseline characteristics and study population.

Prof Mebazaa:
- They were rather classical patients. I mean it's really very similar to trials or cohorts studying patients with acute heart failure. Their age was a little bit higher than 60 years old. High incidence of atrial fibrillation, high incidence of diabetes needed to be included. The NT-proBNP before discharge has to be higher than 1,500 picograms per millilitre of NT-proBNP, and it was much higher than that. Blood pressure was a little bit higher than normal. Heart rate was a little bit higher than normal. Nothing special compared to the patients who are included in all acute heart failure trials, and patients who all of us who were seeing in our daily practise.

Dr Van Spall:
- And what was the median LVEF?

Prof Mebazaa:
- It is a very good question because we decided to not look on the left ventricular ejection fraction. We're taking the patients regardless of left ventricular ejection fraction. And interestingly enough, at the end of the study we had two third of the patients who had a left ventricular ejection fraction below 40%. And one third of patients who had a left ventricular injection fraction that was higher than 40%. And one third with preserved ejection fraction. Two third had a low reduced left ventricular ejection fraction.

Dr Van Spall:
- Any exclusion criteria?

Prof Mebazaa:
- Very few exclusion criteria. The main inclusion criteria was acute heart failure patients who had only one medication, either beta blocker or ACE inhibitor to start. High NT-proBNP level, but very few exclusion criteria.
Dr Van Spall:
- Okay, so hyperkalemia for example, was not excluded or hypotension?

Prof Mebazaa:
- Yeah, we paid attention because we knew that we are going to give a full dose of beta blocker and ACE inhibitor. Then we put thresholds in blood pressure. But again, often patients, which are a little bit de novo heart failure patients who were not well treated, those patients had a systolic blood pressure higher than 120. And for those patients, giving a full therapy did not change so much blood pressure. And in fact, we saw some episodes of hypotension but the decrease in blood pressure in the intensive arm compared to the usual care arm was only a few millimetres mercury.

Dr Van Spall:
- Right, so tell us about your primary outcome and the results of the trial.

Prof Mebazaa:
- The primary endpoint, to try to be as clinically relevant as possible in addition to try to match safety and efficacy, the primary end point was readmission for heart failure or all-cause mortality at 180 days.

Dr Van Spall:
- Fantastic, that's very clinically relevant. You know, many argue that you could have picked surrogate endpoints, like medication doses. But I do agree that a clinical endpoint that is meaningful to both patients and the healthcare system is important. And so, what was the treatment effect on this primary endpoint?

Prof Mebazaa:
- The relative risk was .66 and it shows you that really it was dramatic. Now probably it would have been even more dramatic if the endpoint was longer than 180 days. But really, the concept of the trial is to try to show that we can increase very quickly the implementation of the drugs.
Because everybody agrees that if you combine beta blocker at a high dose, ACE inhibitor at high dose, and spironolactone at a high dose, at the end of the day it's going to have clear benefits on any outcome. But our idea was to show that really the first 180 days would not have a big safety concern, which was the case. We had really few adverse events. Mostly hyperkalemia worsening and in few cases, of kidney dysfunction or hypotension. And we had no adverse event that were really fatal or anything really severe.
And at the end, yeah as we said, the primary endpoint was clearly in favour of the intensive arm. And it was so much in favour of the intensive arm, the DSMB decided to stop the trial because they felt it was unethical to keep having patients in the usual care arm.
And it shows by the way, what maybe we didn't realise for years, that I come back to my analogy with cancer that probably heart failure patients that are not treated are like cancer. They're worsening day after days, and month after months. And clearly, it's probably not ethical, in patients with a clear heart failure diagnosis, it's not ethical to keep those patients over months without being treated.
And even myself for years I was thinking, "Okay, if he's not treated today, we can wait two or three months. At the end of the day, we can manage to have him at full therapy." But in fact, what I didn't realise is for the all the months where the patient, because we had the busy clinic, because we couldn't see him, because many things, during all those months, he's clearly deteriorating.

Dr Van Spall:
- Tell us about the drugs and the dosing achieved in the intervention versus the usual care group.

Prof Mebazaa:
- Let me start with the usual care group. At 90 days, if we see only the medications at 100%. For beta blocker and ACE inhibitor, it was less than 5%. Less than 5% of the patients with the usual care had either beta blocker or an ACE inhibitor at 100%, less than 5%.
In the intensive arm, at 90 days, we were close to 50% for each of the two categories. And now if we look even at the larger range of those going, let's say from 51% to 100%, we can see that in the intensive arm, more than 80% of the patients had between 51% and 100%. And had at least half of the dose to full dose. But again, only looking at the full dose. Close to 50% of the patients at 90 days had the full dose of beta blocker and ACE inhibitor. And interestingly enough, this 50% of patients had this full dose at week two.
Week two, decided in fact there was a turning point at week two. And this reason why I think that there is still room to improve even more than 50%. Because if you see in the paper, it is interesting to see that for all the medications between week two and 180 days, nothing changed. Then it's really psychological thing happening. If we give implementation procedure to the physician, he's ready to follow, you give him all the safety concerns. But after week two, he's happy to put the patient at 50 or 100% because we said that the dose cannot be below 50%. Which was, as I told you, in more than 80% the case. Then in fact that dose will be the dose that we find at 180 days.

Dr Van Spall:
- Now do you have the capacity do you think, in your healthcare system... Actually, this was an international study. So not just your healthcare system, but some might say do we have the capacity to see patients so frequently and with the clinical expertise that heart failure physicians offer across healthcare systems? Is this feasible, is this implementable?

Prof Mebazaa:
- Yeah, it's a very, very good question. I think what is important to STRONG is to show that the concept works. I think we were looking for years on a recipe that helps safely and efficiently to implement a maximum of heart failure therapies at the maximum dose. And I think this, I guess STRONG achieved this. Now in indeed there are several visits and the question that will be raised in the next weeks. But am I able in my heart failure clinics to have four visits in the first three months for a patient? My answer is yes.
My answer is yes because of the heart failure clinics when we are asking a patient to come back, there is no special procedure. Some, you tell them to come back in three months and another in six months and you don't know why in fact. And I think maybe in heart failure clinics we should now, with the STRONG trial, we should focus on the first weeks after being discharged from an acute heart failure episode. And maybe we should now rethink the way we are asking the patients to come back to the heart failure clinics.
Because if the patient comes in the first weeks and if at week two you can already succeed in close to 80% of the patients to be between 50 and 100%, then my question is why do we need to see them again before I don't know, one year or more? Because they are optimally treated or not far to be optimally treated.
Then I think we just need to rethink the way we are doing our heart failure clinics. And my second answer is that maybe those visits do not necessarily all of them, be done by a cardiologist. I think the safety visits can be done by a nurse who knows how to interpret biological tests, who know how to examine a patient, and refer to a cardiologist. But cardiologists do not necessarily need to be there.
Week two is an important visit. This visit at week two, really it has to be done by a cardiologist who have all the parameters, sees the patient, and decide whether he can give the green light for full dose. But if the visit at week one and then the following weeks could be done by a heart failure nurse I guess with no problem.

Dr Van Spall:
- Fantastic. How do we translate this to clinical settings, right? That's usually where the main gap lies. And I think it's the philosophy that the mortality in heart failure is higher than in many cancers. But we have taken it with a grain of salt and not with the urgency that our patients with malignancies receive. And that we need to allocate resources to this type of intervention. We seem to have no trouble offering device therapies that have nominal treatment effects, medical therapies that might not have large clinical benefits. And we know some of the therapies now that do offer benefits so devising systems of care to implement them are well worth our tax dollars.
Thank you for the work of running this trial. I know how hard it is to run implementation trials and to get our colleagues to change the way they deliver care and book patients to see them. Congratulations on your Lancet publication! That's fantastic news and I look forward to being in the audience and watching your presentation later this week. Thank you for joining us Professor Mebazaa.

Prof Mebazaa
- Thank you very much.