This transcript has been edited for clarity.
Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña from Thomas Jefferson University, and this is my blog. I'm thrilled that we're together in person at the American College of Cardiology in Washington, DC. It's been a good 3 years since many of us have seen each other in person. It's been really wonderful to see my colleagues and friends, and I have one of them here with me today.
Dr Justin Ezekowitz and I have worked together on many projects, including the VICTORIA trial, and we suffered through the GUIDE-IT trial. He is a professor of medicine at the University of Alberta in Alberta, Canada. I want to welcome you.
You and I have had so many discussions about the right drugs, but you're presenting the SODIUM-HF trial.
Justin A. Ezekowitz, MBBCh, MSc: That's right. This was a long trial.
Finger-Wagging Patients to Restrict Sodium
Piña: One of my pet peeves about diet is that we're telling these patients, "You have to take all these drugs and now there's four pillars of care, but you also have to cut down your sodium and you have to read the food labels." Then you ask, "Where are the data?"
Ezekowitz: That's the same place I come from, which is, do we have the data to say what I'm recommending is valid?
Piña: And push it.
Ezekowitz: What also stimulated the question, along with whether we have the data to justify our recommendation, is that there's also a lot of finger-pointing and finger-wagging at patients, which is unfair to them and isn't a very patient-centered way to approach it. Let's take a step back.
Piña: They feel terribly guilty.
Ezekowitz: We came at this question with a very honest approach to do a pragmatic trial in this area and test this hypothesis in outpatients with ambulatory heart failure.
Piña: NYHA class II-III?
Ezekowitz: Yes — patients with class II-III heart failure at least a month after the hospital discharge for whatever cause, and they were on optimal medical therapies. These patients are already on whatever was the guideline-recommended therapy for the six countries we enrolled patients from, across 26 sites — so a large amount of heterogeneity as you can imagine.
Piña: Just by country alone.
Ezekowitz: Exactly. Canada, Mexico, Colombia, Chile, Australia, and New Zealand. You can imagine that, in Colombia and Mexico, the sodium content of food is a lot higher. What we also realized is even within regions of the same country, there's quite a gradient. Across Canada, there's a gradient. Across the US, north to south, there's a gradient.
Piña: Most definitely.
Ezekowitz: We designed this trial very simply: usual care, which is what recommendation might be in clinical practice that somebody might have already seen as a recommendation, vs the intervention.
Piña: That's how you defined usual care: whatever the site was doing?
Ezekowitz: Yes, whatever they were doing. We realized we often give that recommendation about salt, but things don't change. There's no real intervention there.
Piña: Do you think the patients get it?
Ezekowitz: They're still eating what they're eating. We started off with the average content of around 2200 mg of sodium per day. This is a well-treated population already eating 2200 mg or so — some much greater, some a little lower. That was usual care. They were starting off at that point.
Piña: How did you keep track of what they were eating at home?
Regional Menus and Food Diaries
Ezekowitz: We thought a lot about this. We did the 3-day food records, which are well validated in the dietary literature, and they reflect what a person is actually eating because we're recording it actively over 3 days. That really helps not only the counseling at the site when they're in the trial, but also it allows us to back-calculate how much sodium, potassium, protein, or calories they are taking in.
Piña: You could average how much sodium were they eating? That's very interesting.
Ezekowitz: Yes. We actually had to go through a fairly extensive exercise to design how we were going to do that and then feed that back to the site.
Piña: Many people have tried to do this. It's very tough. What was your intervention group?
Ezekowitz: We used a series of menus. We took a step back from things like the DASH diet, which included premade meals for people. I think that's very good for a phase 2–like design, but we wanted this to be a pragmatic phase 3 trial.
We had a whole series of menus developed by our dietitian, which are very broad and wide-ranging, so anyone could eat based on their region and what they like. It was very easy to achieve, and we would simply modify the amount of dietary sodium of that menu. That allowed us to isolate that one variable, sodium, while keeping all the other things — the calories, protein, and energy requirements — the same.
Piña: You'll have many substudies out of this with all that information.
Ezekowitz: There is going to be a large amount of information. We're hoping to really understand diet in heart failure. That alone to understand is important.
Piña: How long was the study?
Ezekowitz: For the primary endpoint, we followed people for 12 months. We have a 2-year and a 5- year follow-up for all patients as well.
Piña: Did you just finish the first year, or are you on the second year?
Ezekowitz: All patients have passed the 12-month mark as of December 2021, and many have passed the 2-year mark as well. We have a couple of patients who hit the 5-year mark, but that's a very early set of patients.
Piña: What was the total number of patients?
Ezekowitz: We have 806 patients.
Piña: That's good. Your primary outcome was?
Ezekowitz: All-cause mortality, cardiovascular hospitalization, or ER visits.
Piña: Those are hard endpoints.
Ezekowitz: We chose all-cause mortality mostly because it does reflect 80% of deaths in heart failure. We had to think pragmatically because it's hard to adjudicate death in the first place and it's expensive. Cardiovascular hospitalizations and ER visits were adjudicated using standardized criteria. We kept it as cardiovascular because, although we and other trials use heart failure hospitalization, this was a broader intervention. Diet affects other disease states and not just heart failure. We wanted to keep it very broad and pragmatic. There's always a tradeoff we have to make in every trial.
Piña: You make the tradeoff, you write it down, and you keep going.
Ezekowitz: I'm looking forward to digging into the data because there's a large amount of information on the events as well as the noncardiovascular events.
Piña: Tell us what you found so far.
Ezekowitz: The primary endpoint overall was nonsignificant, with a hazard ratio of 0.89.
Piña: An 11% reduction, though.
Quality of Life Improved, Counterintuitively
Ezekowitz: It's true, and the conservative interpretation is that it's a neutral trial. But there's still an 11% reduction in the composite endpoint.
All-cause mortality individually, not different; hospitalization, not different; ER visits, not different. There's a signal that looks like it does reduce hospitalizations, and that had the greatest impact on the overall composite for the primary outcome.
For the secondary outcome, the really interesting parts are the quality of life and NYHA class. As a clinician thinking about NYHA class, we did see an improvement in NYHA class by at least one category in the low-sodium diet. The odds of that happening were 0.59, so we're very impressed by that change in NYHA class.
From a patient perspective, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall, clinical summary score, and physical limitation score was about a 3.5-point difference between the groups.
Piña: About the same as most of the drugs.
Ezekowitz: Yeah, same or better than many of our drugs. I think that quality-of-life difference favoring the low-sodium arm is significant. I think it is meaningful. It's a question of it's a secondary endpoint and we have to balance that against the overall trial results.
Piña: You would think that if the patients are allowed to eat whatever they want, maybe the usual care group would have the improved quality of life because they don't have to worry about what they're eating and counting the sodium.
Ezekowitz: At the very beginning of the trial, people said, "If you make them eat a low-sodium diet, it will worsen their quality of life."
Piña: That's what you would think intuitively.
Ezekowitz: We faced some uphill resistance on that. We measured it, and we wanted to make sure we measured it and it's the other way around. Patients may actually feel better on a healthier diet.
Piña: They don't realize it until they're there.
Ezekowitz: It shows that we have to counter our own intellectual biases. Sometimes we have to challenge them and do the trial.
Piña: When or where are you publishing this?
Ezekowitz: It was published simultaneously in The Lancet.
Piña: You have a worldwide population, so that's a very appropriate journal. What will you do next with the data?
More to Learn on Diet in Heart Failure
Ezekowitz: We have 1000 secondary analyses to understand this population better. We've already looked across geographic regions, and there's no clear signal.
Piña: How many women did you get?
Ezekowitz: One third of the population was female. The average ejection fraction was 36%, so when we looked at the epidemiology, we were close but not ideal. We wanted to get a better balance. It's a challenge. We can only control what we can control. We have an excellent representation of women on the steering committee, at the site level, in the food core lab, in events adjudication. Everything across the line was very much focused on making sure we had appropriate equity and representation.
Piña: That's really important. I've spent so much time in 30 years saying to the patient, lower your sodium, look at the labels. When I was at Temple, we actually had people add up their sodium from what they were eating. Nowadays, I tell them that I want you to cook primarily at home. Put only a little bit of salt in your food, which is essentially a 2-g sodium diet, and avoid the deli. Other than that, I want you to take your medicine.
Ezekowitz: I think you've got the right approach, which is to keep it simple. My usual simple one is to avoid anything in a bag, a box, or a can. For most patients, that helps us frame what they should avoid.
Piña: They understand that.
Ezekowitz: If I had to follow dietary recommendations, I would have to really think about it. I don't have heart failure, so I don't have that barrier.
Piña: Or that worry that you will get sicker if you go off the diet. It is not just that today you'll feel a little sluggish.
Well, congratulations. This is really hard. A long time ago, there was an NIH proposal for a very strict dietary trial looking at sodium, and it never passed muster and never got funded because it was so hard to do.
Ezekowitz: These are hard trials to do, but they are so important. This is fundamental to the way we live. We eat food, so if we can modify this one thing, does it make a difference.
Piña: Kudos to you. Examine the women separately. You have enough to maybe make some statements about it. Because women do control the house and they usually control the kitchen, it would be very interesting to see how they did.
Ezekowitz: I'll tell you what we've done so far. We're going to dive deeper into this, of course, but our initial look was to make sure we did a couple of things. In a subgroup analysis of men and women, there was no large signal there. For the quality of life, we've done a sex-stratified analysis to make sure we weren't missing an important difference in one or the other. It was really not different, but we're going to dig into that more.
Piña: Keep us in mind for another blog when you've done more, so that we can tell our audience, because this is interesting to the clinician.
All of you listening today can take heart that when you forget to give the recommendations for dietary sodium, maybe it's not quite as important as we all think it is. If you can keep it simple, the patients may be able to follow better.
This has been great. Thank you for joining me today. This is Ileana Piña signing off. Have a great one.
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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Cite this: SODIUM-HF Simplifies Message to Patients on Diet - Medscape - Apr 08, 2022.