Javed Butler discusses the details of the trial on empagliflozin in HFpEF with Ileana Piña and what might be learned from the subgroup analyses.
Hello this is ileana pina we’re talking today about the european society of cardiology meetings which happen every year toward the end of august and usually a lot of impactful papers are presented there that really do change how we treat and see patients and how we see the disease process so this is my blog i am thrilled to have a good friend with me today dr javed
Butler a good colleague and chair of internal medicine at the university of mississippi in jackson uh he’s had some other hats before that but this is his most recent hat and obviously a very important one in an area where their their research and the jackson heart study is absolutely impactful uh and very very important to what we know today but javed is going
To talk to us a little bit more about hefpef heart failure with preserved ejection fraction something that we have discussed before on this blog and and the frustration sometimes that we feel when trying to treat these patients because we haven’t had that whopping great drug that we can say this is it however we were very encouraged when we heard that the emperor
Preserved trial of empagliflozin had reached its milestone and that it was positive and so we were all very excited to hear about this and javed and our other colleague stefan anker have really been at the head of this so javed welcome a little longer introduction but uh we’ve talked about this on my blog before about the importance of hefpef and how we have never
Really nailed it uh because i wonder if we’re even talking about the same thing so tell us a little bit about this and why this is so important and what is the drug yeah so thank you very much for for inviting me great to talk to you so this trial uh uh ember preserved uh looked at uh sdlc tournament empire closing in patients with heart failure preserved ejection
Fraction which was defined as ef greater than 40 the trial was designed to answer three questions so the power calculations and the design was for three questions one uh time to cardiovascular death or heart failure hospitalization then total heart failure hospitalization so cardiova first and recurrent and third was renal function preservation or egfr slopes having
Said that obviously while this trial was being done uh science continues to progress so there were a bunch of subgroups although the trial was not designed for it we did not necessarily have the power for it but a bunch of the subgroups uh became really interesting in the field of half craft so one is is there a difference between 40 to 50 versus greater than 50
Because the data are coming out looks like 40 to 50 is different than 50 plus then the other was the sex page differences that it looked like from some of the other trials that maybe half pep should be defined differently between men and women and that maybe women respond more uh than men so those are the kind of things and then the issue of obesity comes up as
Well so with that background the trial was done you know typical large trial 6000 patients global trial and what we found that the trial hit all its three predefined endpoints so the time to cardiovascular death heart failure hospitalization 21 relative risk reduction highly statistically significant total heart failure hospitalization 28 relative risk production
Again highly uh statistically significant and both of them uh we we will agree is also clinically relevant also 21 and 28 relative risk production and then the egfr slope also was significantly preserved about 1.36 ml per minute per year so overall the trial achieved all the three goals that it was intended to look for but then comes sort of the site uh the the
Subgroup analysis that becomes of interest so i i say this with some reservation because these data are new we really have to digest it and we haven’t done that completely but the bottom line is that for primary endpoint there was no heterogeneity noted on the basis of sex or on the basis of ef less than or greater than 50 so that’s good news that we may have a
Heart failure with preserve ejection fraction drug that works across the spectrum of these subgroups however we did not achieve the cardiovascular death benefit there was a nine percent directional benefit it did not achieve a cardiovascular debt a clinically significant result but i’m sure we’ll learn a lot uh from secondary analyses of these data then deliver
Trial adaptive disclosing will be coming out as well uh so so the dialogue will continue so javed uh you brought out two very important points and i was very happy to see that the effects seem to be very balanced between men and women i think that that’s a very important piece since we know that the primary population of real half is women um and and women that
Are very hard to control and very hard to get them feeling better even i’m not surprised about the mortality because what we’re seeing nowadays is that a lot of these trials that we’re seeing with a lot of different drugs affect hospitalization but do nothing to mortality maybe we have reached the the best mortality benefit that we can achieve with what we’ve done
Before and and nothing new will come out of it except that symptoms in this population is really really important so tell me a little bit about and you know i’m going to ask you this about the group over 50 because you did have some that are between that 50 and 60. yeah yeah so there was actually a pretty sizable proportion almost a third third third split between
Uh 40 to 50 50 to 68 greater than 60 and the interaction key value was 0.21 and the hazard ratio is less than one for all of these three groups now obviously as you go across the spectrum of ejection fraction uh you start seeing the change that that you have alluded to anyway so you have more women and you know higher ef less in the lower ef more obesity in the
Higher ef lower are in the higher uh ef group so so these are the changes that we really need to dissect a little bit more i am sure when we get some time to digest these data this heterogeneity in half half because the trial is positive in all subgroups doesn’t mean that the heterogeneity goes away i’m sure within this trial also there is heterogeneity but we
Just need a little bit more time to digest and understand these things but overall we did not see a difference i think it’s it’s a very important group because it’s a group that we commonly see in the clinic again many of them women many of them obese and many of them hypertensives that have had hypertension for years and we make this diagnosis based on symptoms
The shortness of breath with activity uh obviously if we could have catheters in and we could see how high these la pressures go whenever there’s some movement and now we’ve been talking about cardiac rehab for this group with an important trial and we’ve interviewed delane kitzman on this program as well but this phenotype idea that people keep floating we need
To have phenotypes for hefpef what would you say to that well so first of all phenotype with the strictest definition is what we sort of observe in front of our eyes what we really need is to understand understand the various pathophysiologic pathways that drive the outcome so it’s a little bit of a different type and i think we will learn that so that we can have
More targeted therapies obviously the most obvious example is amyloidosis and how much we are learning so but the big question is are there more such amyloidosis kind of hidden pathophysiologies that are different diseases within half craft and i think we will understand a lot in this omics era where we can understand the biology of the disease a little bit better
So that’s one way of sort of thinking about phenotype the other way of thinking about phenotype is that some people based on their all the comorbidities and demographic characteristics and whatnot have a phenotype that is more likely to respond or less likely to respond and that is sort of a no-brainer that if you look across these groups of patients of course
Some people will be more advanced less advanced will have a mix of comorbidities that may just be more or less responsive and of course that science will progress so but i do want to highlight that we use the term phenotype sometimes a little bit more loosely and we mix these two concepts together yeah what about uh the weight uh did you exclude remember paragon
Excluded the very obese which i when i did paragon i couldn’t get the patients in because all of my women in new york were obese uh so what did you do with bmi and weight in empire uh we did have an exclusion criteria and i think it was also 40 but i may need to check that 40 or 45 i think it was 40 but but we did exclude also i mean you and i have talked about
This i think that group across all the trials that have happened we need to look at that group of particularly women with those higher efs with that history of hypertension with that obesity and then a final question for you tell me about the aging of the heart these are all older and and the this group up there is is in the high 70s what’s happening with just
The senescence of the heart you know the ed lakata uh aging of the heart yeah so i mean if you sort of think about it all the therapies that i’ve worked in patients with heart failure with ras modulation aldosterone and with beta blockers before that none of these are really targeted therapies they have really systemic effects and they improve outcomes so when
You come to sglt2 inhibitors while they may have been discovered as anti-hyperglycemic therapy if you look at the entire pharmacodynamic profile in terms of its effects on the cardiac structure and function in terms of its effect on the vascular structure and function eliposity and the renal function all of these things get worse with aging endothelial function
Aortic stiffness fibrosis compliance and exactly so all of these things and sgl due to inhibitors have beneficial effects on all of these things so i’m not surprised that this sort of mixture of obese order and half half populations uh that also have ckd benefit with israel these two inhibitors i also am always amazed when i see all the sglt2 data across is
That we don’t recognize often how much renal function the patients are losing until we do something like this look at it across time and the fact that there’s preservation of renal function to me in long-term outcomes maybe that’s why the mortality doesn’t really drop a lot because we’re not harming the kidney on the contrary we’re protecting the kidney well
But also i mean a couple of very quick comments you know one is that at the end of the day we don’t have the appetite to do really long-term trials right so if you’re going to look at the mortality benefit this is not the 1980s 1990s trial which were powered only for mortality these straws are kind of powerful combined endpoint and the minute you hit the number
Of combined endpoints you stop so that is difficult to say and then on terms of the sort of the the the renal function comments you made i mean you know it’s it’s a little bit humbling to say that you know there’s a lot of things that we don’t do in the clinical practice and we don’t screen and we don’t have the data but this gfr business i mean every single
Patient that we see every single time has estimated gfr and electronic medical record but you don’t have that mindset to track the gfr and the decline and act accordingly having said that there is so much interest in the field of ckd that hopefully that dynamic will change and i hope that uh the trial continues with long-term follow-up i don’t know if you uh the
Group has decided to do that but i think would be very interesting to see say in a couple more years and 24 more months what what has happened to those patients i want to thank you for your time i know it’s a busy time for you we have some very interesting papers coming out of the esc and i’m hoping to work with you on those higher ef patients as well so jobette
Congratulations to you and stefan on a well-done trial and uh the first time that we can say you know that these groups really do benefit i think it’s a wonderful i think it’s a wonderful thing so thanks for joining us into my audience i hope that you can apply this to your practice i hope that when you look at the patients you look at them as individuals we’re
All trying to practice precision medicine and remember that stability is nothing more than an illusion in heart failure thank you for joining me today have a great day you
Transcribed from video
Empagliflozin in HFpEF: Putting EMPEROR-Preserved in Context By Medscape
