This transcript has been edited for clarity.
Ileana L. Piña, MD, MPH: Hi. This is Ileana Piña from Central Michigan University, and this is my blog. With me today, fresh from the American Heart Association (AHA) meetings, is Dr Eldrin Lewis. Dr Lewis is the chief of cardiology at Stanford, a position that he's been in now for about a year. Is that right?
Eldrin F. Lewis, MD, MPH: About a year and a half.
Piña: I've asked him to talk about the CHIEF-HF trial. In this blog, you have heard me, many times, talk about health status and quality of life and about the SGLT2 inhibitors. These drugs are impressive because they do so many things, but they primarily keep people out of the hospital. We've had assessments of health status coming in trials for empagliflozin. At the AHA meeting, we heard about dapagliflozin, sotagliflozin, canagliflozin.
Eldrin, tell me about the CHIEF-HF trial.
Lewis: First of all, thank you very much, Dr Piña. It's truly a pleasure.
The nice thing about it is that the entire study was done without a face-to-face visit. The reason I think that's important is because it gives access to patients who may not be able to go to your traditional healthcare centers because of the distance traveled, the cost, etc., so you can reach out and actually meet the patients where they are.
The second thing that I really liked about it is in terms of inclusion criteria, it's very simple. If you had an iPhone 6 or later model or a Samsung 7 or later, you're eligible, and you had to be willing to wear a Fitbit.
The last thing, which I think was really important, and I've been a strong advocate of this for a long time, is that if we're trying to look at improvements in health status, we should enroll people who actually have impairment. This study required a Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of ≤ 80. If you had a higher score than that, then you need not apply because it's harder to show an improvement in quality of life if your quality of life is quite good.
Piña: How were the patients selected?
Lewis: If they basically had electronic medical record evidence of a heart failure, whether preserved or reduced ejection fraction, then they received an email, a phone call, or any other access, or even at a visit to say, "Are you interested?" If so, the patients could go to a website and look at the details of the study and say, " I'm interested" or "I'm not interested."
Once again, it puts the power in the patient's or participant's hands instead of having everything done by site investigators, and in general, about 50% of people who screened in consented. That's a pretty good hit rate.
Piña: That's very good. I expected less than that.
Lewis: One of the things that I really liked — and I wonder if it's in part because of this trial design. They didn't report ethnicity so we don't know the percentage who were Hispanic, but we know that 14% of the participants were Black, 45% were female, and about 59% of patients had heart failure with preserved ejection fraction.
You did have a wide range of people and you also had people with or without diabetes. Out of that, about 28% of the people who consented actually screened out because their health status was too good. That's a good thing because that means that they're actually doing okay with their heart failure.
Piña: It means your selection is a little bit tighter.
Lewis: That's exactly right. They randomized 476 people to canagliflozin vs placebo and followed them for 12 weeks on treatment, looking at changes in health status. Beyond the scope of this discussion, they will follow these patients long term. They're going to follow them out to 9 months with KCCQ, global assessments, patient satisfaction, and exercise capacity.
Piña: The exercise is measured by the Fitbit?
Lewis: That's exactly right.
Piña: The Fitbit gets reported in.
Lewis: The original plan was to enroll 1900 patients, but they didn't. Even though it's a site-initiated, investigator-initiated study, the sponsor basically had competing goals. They only analyzed 448 people.
Piña: That's a shame that they only got that many.
Lewis: For quality of life, that actually gives you reasonable power, but in terms of looking at secondary analysis and subgroup analysis, it makes it really challenging.
Piña: I saw that the baseline KCCQ numbers were in the 50s. Having used this instrument for many, many years in my own clinic, I can tell you that the 50s is what the patients leave the hospital with. When I see them at their first post-discharge clinic, their scores are generally in the 50s, which means they're impaired. It's not a great quality of life.
Tell me the results as you saw them.
Lewis: Just to put this into perspective, there have been four studies so far that have published quality-of-life data using the KCCQ with SGLT2 inhibitors, and that's the DAPA-HF, the EMPEROR-Preserved, EMPEROR-Reduced, and DEFINE-HF. Basically, the score changes range from about 1.5 in the EMPEROR-Preserved study all the way up to about 4.8 in the DEFINE-HF study. There were many in between.
Piña: You're talking about the difference between placebo and drug.
Lewis: Exactly right. Thank you for clarifying that. It's important to test against placebo when you're trying to look at the effect size because just the hope of a therapy actually improving outcomes can change quality of life, and we've seen this time and time again. The effect size is much smaller when there is blinding.
In this study, it showed about 4.3-point improvement compared with placebo, which is actually pretty dramatic. They did a responder analysis where they look at the number needed to treat for a large improvement, which they defined as a 10-point or greater improvement. You need about 27 patients in order to get that significant change in their quality of life. If you look at the deterioration of 10 points or worse in their KCCQ score over the 12 weeks, you'd need to treat about 15 people to avoid a deterioration (basically to preserve their overall health status).
Piña: The numbers are quite reasonable. If they see something in the Fitbit, that would be fascinating.
The issue that I have is that many of these patients may not have been in the hospital [recently], but they got selected from the electronic health record so they may have been in the hospital [at some point]. Do you have any idea how many of them have been hospitalized?
Lewis: No. I think that's an important point. Hopefully, it will be captured in the manuscript [when published]. If you were discharged from the hospital recently, we know that your scores changed. If we compare the other four SGLT2 inhibitor studies that used the KCCQ, the median score was around 77 to 82.
Piña: Way high.
Lewis: In fact, in one of the trials, EMPEROR-Preserved, about 25%-30% of patients actually had a score of 90 or higher. These patients are not impaired.
Piña: Not at all. I've equated it to the New York Heart Association classification. You can see that as the NYHA class worsens, the scores go down. My issue is, how do you capture, in a questionnaire like this, the effect of the SGLT2 inhibitors? The SGLT2 inhibitors, as far as we know, don't necessarily change symptoms. Maybe there is a little bit of diuretic effect, but they don't really make you less short of breath in the way an ACE inhibitor does or an ARB or an ARNI. Beta-blockers may make you more short of breath early and then better later.
How do you capture the absence of a hospitalization?
Lewis: You can't measure that without having another instrument, but we've published several times the impact of nonfatal events. There's been so much focus on death with heart failure and prevention of death with heart failure because it was such a lethal disease and remains that. Now, since we've dramatically improved their survival, we need to transition to how to get people to live better with quality of life. One of the things is to capture these nonfatal events. We were able to catalog the impact of a hospitalization, and you see a dramatic reduction — about a 12- to 15-point reduction.
Piña: Oh, it's huge. I've done it, I've seen it. But the absence of the hospitalization, I don't know how to quite capture this, but these are discussions for a good editorial by you. I'm going to suggest you for a good editorial on this.
Lewis: I would love to. I would say there are two ways to do it. I think the first is to look at the group of patients who over the 12 weeks were hospitalized for any reason. Then within that hospitalization, look at the change score between canagliflozin and placebo. Then you look at the people who are "clean." They lived at home with their heart failure. They never were hospitalized and never went to the emergency department. You need really good case reports for this.
Piña: To see what happens to them.
Lewis: In the absence of a heart failure hospitalization, do we still see a significant change? I think that's what we need for the SGLT2 inhibitors because you see such a dramatic drop [in hospitalizations]. The last thing is that we do see a significant diuresis effect with these SGLT2 inhibitors.
Piña: It happens really early.
Lewis: Right, and in the CHIEF-HF study you saw early separation within 2 weeks, and you wonder if some of that could be the decongestive component. And then the persistence could be they feel better.
Piña: Yeah, they feel better.
Lewis: That mechanism needs to be teased out.
Piña: I think we still have a large amount of work to do in this area. You and I have been very interested in this area for a long time, so I think we are not going to be out of a job anytime soon. There's much to do. Eldrin, I want to thank you for joining me today.
I'm hoping that our audience captures how important it is to assess your patient's health status because we all know the ejection fraction and the blood pressures, but what is the impact of the disease on that human being? What has happened to them, even in their sense of quality of life? I think that's an important message out there.
It is not only this instrument; there are other instruments that you can get, such as the Minnesota Living With Heart Failure Questionnaire, which you can just download and sum it up. Use it in your offices to get a sense of what your patients are really experiencing outside of all the demographics that we all know.
Again, I want to thank you, and best of luck on your position at Stanford.
Lewis: Thank you.
Piña: This is Ileana Piña. Thank you for joining me today. I hope this is useful for your practice. Have a great day.
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: Ileana L. Piña, Eldrin F. Lewis. CHIEF-HF: No-Touch Initiation of Canagliflozin in Patients With Heart Failure Improves QoL - Medscape - Nov 24, 2021.
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