Professor Thomas Lüscher discusses the paper of the week with Brian Halliday
Hello this is tom luscher talking to brian holliday at the royal brompton hospital and today we would like to uh discuss specifically a recent paper presented at the european society of cardiology this year by stefan unker and milton packer the emperor preserved trial uh on ampergliflozin in heart failure was a preserved ejection fraction welcome brian thanks very
Much so uh we all learned that this sodium glucose transport inhibitors are highly effective in heart failure but so far it was mainly in patients with heart failure with reduced ejection fraction that these drugs were tested directly now this new trial tries to do this in preserved ejection fraction which in their specific case meant that the ejection fraction
Would be higher than 40 percent so uh according to the new asc guidelines this is both ref the tongue breaker that now is renamed as a ejection fraction a mildly heart failure is mildly reduced ejection fraction and true have path above 50 percent so let’s brian why don’t you look at uh at the patient population these are around close to 6 000 patients
Randomized to amperglipflozin and placebo what can we say about the patient population yeah so a really huge patient population a real feat to be able to recruit almost 6 000 patients so as as we can see they’re they’re an old population so an average age of 72. um as we expect with with with patients with heart failure preserved ejection fraction around a half
For women perhaps who would have expected even more than than a half of women based on the some of the epidemiology we knew with with heart failure preserved ejection fraction being most common in in women perhaps that’s also driven slightly by the fact that there was also the mildly reduced ejection fraction patients which which is is perhaps more akin to the
Reduced ejection fraction group and the the majority of patients with three quarters were were white um just a small number of of black patients under five percent um so so again perhaps some difficulties in extrapolating the evidence to other populations apart from apart from like caucasian patients um and and there was most most patients were recruited in
Europe so so almost 50 percent of patients latin america got almost a quarter of patients so some impressive recruitment from latin america too about one in eight patients recruited from north america and and and fairly typical mha class so the vast majority of patients were in class two and a small number in in class three at around 20 percent yes and very
Very few was very severe heart failure which is also so interesting yeah yeah okay uh so uh and uh let’s look at the uh at the main results uh that are shown here what can we say here um so overall there’s a 21 um reduction in the primary input to the primary endpoint as with as with um other sglt2 inhibitor trials like dappyhf and and emperor reduced and
Was a composite of cardiovascular death and hospitalization for heart failure or or an urgent visit for heart failure requiring diuretics so there’s 21 risk reduction and and this was highly statistically significant and the curve seemed to separate very early on so that so there seems to be an early effect um and which is which is pretty impressive if we dig
A little bit further down into the composites of the primary endpoint we see that that this was driven by a reduction in hospitalizations for heart failure and indeed there wasn’t a reduction in cardiovascular death that that perhaps we saw with um daphia jeff in the reduced ejection fraction group so in this group of patients with preserved ejection fraction
The the primary endpoint reduction is driven by by heart failure hospitalizations and how does it compare to uh to adapt to patients with uh half ref in terms of number of hospitalizations so overall the the event rate is it seems to be about 10 to 12 months in in the placebo arm and in dap hf the the the event rate was slightly higher than that it was 15
Percent so so the number of events seems to be slightly less in in this population and and perhaps that’s not um completely unexpected um given given what we know about the populations with the reduced ejection fraction who primarily have a a primary cardiac disease and then this group of patients which are more of a heterogeneous group we have hospitalizations
For a number of other reasons as well as as well as heart failure what’s impressive as you mentioned is that these early divergence of the curves and that also was seen with the other trials with sodium glucose transport inhibitors wasn’t it yeah yeah absolutely so um i i i think we’re still unraveling exactly how these um agents have their effects and people
With heart failure and and there’s lots of potential mechanisms driven from from from um pre-clinical research um we know that they have a slight diuretic effect and and you know it is the magnitude of the effect we see here early on too much for it just to simply be a diuretic effect and and how else could it produce such a rapid effect other than diuresis and
And these are all interesting questions that perhaps we don’t have perfect answers for yes yeah we don’t have good comparisons with what a diuretic would do instead huh no absolutely because these trials are not done because they’re all generic and nobody wants to fund it i guess yes all right so let’s move to the um uh subgroup analysis that we have here uh
Overall effect we we said and diabetes or with or without diabetes that’s a common picture with the sodium glucose transport inhibitors in heart failure it doesn’t matter whether you have diabetes or not isn’t it yeah yeah absolutely you know it’s consistent with the other evidence and you know suggest we should be using these regardless of of diabetic status
Right what about this ejection fraction uh picture what can we say there so i think this is really intriguing and um i suppose it’s when you look at this forest plot you you wonder whether the the effect attenuates at higher ejection fractions and indeed from the presentation with with the emperor pulled analysis who pulled analysis from booth emperor reduced
And emperor preserved the effect in reducing heart failure hospitalization seems to be lost when your ejection fraction gets above 65 so again perhaps there’s an attenuation of effect or even loss of effect um at higher ejection fractions and perhaps we need to be using a cutoff of 60 or 65 percent um and focusing on those patients with an ejection fraction below
That yeah i mean coming back to the definitions of heart failure according to the new 2021 esc guidelines presented by terrorism mcdonough and marco metro at the european society of cardiology this year you would say that the first group below 50 is actually heart failure as they call it now is mildly reduced ejection fraction so you have a most dominant effect
It’s a bit less than in half ref which makes sense because they’re less sick but uh that’s what you could say and then uh of course the the next that strata over 50 to less than 60 just barely made it with a confidence interval of 0.64 to 0.99 while as you mentioned when you go above 60 percent the effect is lost and is this still a group of patients that
Needs uh specific treatment do you think so i think i suppose i have two questions when i think about the group with ejection fractions above 60 or 65 percent and the first one is do they truly have heart failure um so the inclusion criteria for this trial was an nt proof bmp above 300 if you’re in sinus rhythm or above 900 if you’re in af so could you be as a
75 year old with breathlessness with an anti-probiemp of 350 and not truly of heart failure and and are some of these patients with with low atrial fibrillation with with shorts of breath due to something else and on high-end heat-proof bmps driven by their atrial fibrillation um and then maybe the other question is what’s the cause of their heart failure and
Do some of these have phenocopies of of different things that maybe actually have specific treatments um or some of those patients with with non-sarcomeric hypertrophic cardiomyopathy who have hyperdynamic ejection fraction typically and perhaps don’t respond um or respond in different ways to to neuromural inhibition to compared to patients with with reduced
Ejection fraction uh maybe some of them also have hypertensive heart disease possibly and yes then the other striking finding is that this mainly works in the elderly is this because there were more patients obviously but not hugely more i mean still in the younger group below 70 it’s more than a thousand patients so it’s it’s not not a small group how
Do you explain that i think it’s you know an intriguing hint that you know there may be a particularly strong effect in elderly i i do think we can read too much into it until we understand more about exactly how these agents work and and why they may work more more strongly in elderly patients um you know i i think for the moment we should be giving this to
Any patient regardless of their age and certainly not withholding it in in elderly patients and you know giving it to even a development and then of course we have this tendency that females have a greater effect that’s what we saw also in others trials didn’t we yeah too again we’ve got lots to uncover about sex differences in in in heart failure i i think
From the interest to um trials we saw that interesting may have effects at slightly higher ejection fractions than women and perhaps that’s because the true ejection fraction in women or the the normal ejection fraction is women is slightly higher than in men um again there’s there’s there’s lots for us to to uncover and you know it’s a it’s a rich area for
For research in the future yeah yeah so uh we can really say that these uh drugs the sodium glucose transport inhibitors are an amazing new armamentarium for us as treating heart failure with or without diabetes and indeed in the new asc guidelines they are at the same level now as uh the classical drugs we’re using like the ace inhibitors or rnas and the
Beta blockers and minor corticoid antagonists so we have really four pillars in heart failure to uh to treat these patients and um this is truly a a uh important uh progress in this field of cardiology so thank you very much brian it was a pleasure to talk to you and i hope our audience also uh enjoyed this discussion so thank you bye bye
Transcribed from video
Empagliflozin in Heart Failure with a Preserved Ejection Fraction By InsideCardiology
