Hello. I'm John McMurray from the University of Glasgow. And today I'm going to talk about the clinical challenges we face in initiating guideline recommended therapy in heart failure.

So these are my disclosures.

Now there are many barriers and challenges to implementing new treatments in patients with heart failure and I've broken them down into this slide into the barriers faced by physicians, barriers faced by patients, economic barriers and barriers related to the health care system.

I clearly can't talk about all of these today and what I'm going to focus on, firstly are concerns related to tolerability, because those are shared by physicians and patients.

And the three main concerns with most heart failure treatments are about blood pressure being too low, about worsening kidney function, and about hyperkalemia. Often these are more imagined than real and we'll come back to that. And then for the treatments that we're talking about today, SGLT2 inhibitors. There's a very specific concern which is about ketoacidosis.

So let's look first of all at blood pressure and concern about causing hypotension. Well, this isn't something to worry about with SGLT2 inhibitors. Because in fact, the average decrease in blood pressure with these drugs is very small. Here in the DAPA-HF trial, you can see that the average decline in systolic blood pressure was about 2.5 mmHg.

Now, in fact, the interesting thing is that, if you look carefully at the figure here, you can see that the patients who started with the lowest systolic blood pressure, shown in the lilac color, people with a systolic blood pressure of less than 110 mmHg, they actually had a smaller decline in blood pressure than patients who had a higher starting blood pressure. So it's a small reduction overall, and people who have got a lower blood pressure to start with tend to get even smaller reductions.

What about kidney function? Clearly, this is a very big problem in patients with heart failure. We all know how common renal dysfunction is in our patients with heart failure. But again, there really isn't a concern with SGLT2 inhibitors. Here you can see the decline in eGFR over time in the DAPA-HF trial. What I've done is, I've broken out the patients into four eGFR categories. You can see at the top people with a relatively normal eGFR, and at the bottom people with an eGFR below 45 ml/min/1.73m2 and the overall average decline in GFR was only 3 ml/min/1.73m2 . And as you can see, the decline in patients who started with a low eGFR was, if anything, smaller. And in fact, if you focus in on the around 700 patients that we had with an eGFR between 30 and 45 ml/min/1.73m2, you can see that the average reduction in GFR was only 2.4 ml/min/1.73m2, and very few patients had a substantial decline in eGFR. And only 5 patients, 0.2%, had an eGFR decline to 20 ml/min/1.73m2 or less. So again really nothing to be concerned about with respect to kidney function.

But this is maybe the most important slide I'm going to show you in this presentation. It looks complicated but it really isn't. So along the bottom of the slide, you see various definitions of a decrease in eGFR. There are two bars for placebo. Placebo is shown in blue. There are two bars for SGLT2 inhibitor treatment, dapagliflozin is shown in red. And you can see that in patients receiving placebo who had a decline in eGFR, so that's shown by the hatched bar, you can see that those patients did worse than patients who had no decline in eGFR, who had no worsening renal function. Those are shown by the solid blue bars. Now, contrast that with the patients receiving dapagliflozin, the patients who had a decline in eGFR, who had worsening renal function, so they're shown by the red hatched bars, They had, if anything, a better outcome than those demonstrating no change in eGFR. So a completely different pattern between SGLT2 inhibitor treated patients and placebo treated patients, If you have a decline in the eGFR early after starting placebo that predicts a bad outcome. On the other hand, if you've an early decline in eGFR, with an SGLT2 inhibitor, as you can see, your outcome is not worse, in fact, it tends to be better. So, even the small declines in eGFR that we do see in some people who receive an SGLT2 inhibitor don't matter. In fact, if anything, they predict that those patients are going to have a better outcome. And of course, you've got to remember that in the long term, these drugs slow the rate of decline in eGFR. So, after that initial dip in eGFR, as you can see the rate of subsequent decrease in eGFR over time is actually significantly less in patients getting SGLT2 inhibitor than patients getting placebo.

So the things to take home about changes in eGFR with SGLT2 inhibitors. Is that overall the change is small, that the decline probably reaches the minimum at about two weeks after starting treatment and partially reverses thereafter, it's not associated with a worse outcome in patients getting a SGTL2 inhibitor and in the long run, these drugs slow the rate of decline in eGFR.

Now, what about hyperkalemia. Clearly a concern with particularly drugs inhibiting the renin-angiotensin-aldosterone system. Well again, this is not something we need to be worried about with SGLT2 inhibitors. You can see that, in fact, the incidence of serious hyperkalemia, that's a potassium of 6 mmol/l or above. You can see that that risk was actually significantly less in patients getting a SGLT2 inhibitor than in patients getting placebo. And in fact that benefit was most marked in patients receiving concomitant, mineralocorticoid receptor antagonist treatment, MRA therapy. So again, potentially very useful synergy between these drugs. Hopefully SGLT2 inhibitors, helping us avoid hyperkalemia in patients getting MRAs.

So lastly, there's a very specific concern about ketoacidosis in patients getting SGLT2 inhibitors. But in fact again, this concern is perhaps over-exaggerated, because if you look at the trials, and you can see them all summarized in this slide, the incidence of ketoacidosis is extremely low overall, and really isn't significantly different in the SGLT2 inhibitor group compared to the placebo group.So it does happen occasionally, but it doesn't happen commonly. And to give you some perspective on that, at the bottom of the slide, you see the risk of angioedema with ACE inhibitors and with Sacubitril/Valsartan, and again the perspective here is that the risk of ketoacidosis with an SGLT2 inhibitor, is probably even less than the risk of angioedema with an ACE inhibitor or Sacubitril/Valsartan.

So, I'm now going to switch to one final topic, and that's looking at another type of barrier or challenge and that, of course, relates to physicians and what physicians think. And this is about workloads, something called inertia and something called nihilism. So, let's start with inertia, inertia means our human tendency to do nothing, to really not change things as sort of our passiveness or inactiveness. And clinical inertia is a really big problem for our patients and is indeed one of the major barriers to implementing any new treatment. These are examples of things that I'm sure you've heard your colleagues say, maybe you've even thought them yourself. These are the sort of reasons that we give ourselves for not implementing new therapy, but they're completely false. So the idea that patients are stable, is false. You can see here in the PARADIGM-HF trial, these patients with generally mild symptoms, very well treated. If you look at the Sacubitril/Valsartan arm, you can see that those patients had a very high event rate over about three years of follow-up. And in fact, if we looked at our expanded composite endpoint, looking at all forms of worsening heart failure, you can see that that risk in the Sacubitril/Valsartan group shown in the right-hand panel of this slide was about 30% at three years of follow-up. So even patients with so-called mild symptoms, who are extremely well treated have a very high event rate. So they're not stable, they need more treatments.

And if you don't believe those data, then look at what the patients themselves are telling us. If you look at the two bars, to the left of this figure, you can see placebo treated patients in DAPA-HF reporting a five or greater point change in their KCCQ Total Symptom score. These are the patients reporting a decrease, that's a deterioration. And you can see in the placebo group that proportion was 33% at eight months. There are 33% of our patients when they fill in that questionnaire, tell us that they've deteriorated within just eight months of being randomized in this trial. And yet again, these were extremely well-treated patients with generally mild symptoms.So they're not stable, they do deteriorate.

It's never too late to introduce a new treatment. Even as long as five years after diagnosis in well-treated patients, who seem to be doing well in conventional therapy. You can reduce risk further with a SGLT2 inhibitor.

Now, I just want to finish by saying something about this concept of therapeutic nihilism. And what do I mean by that? Well these are examples of sometimes again you hear your colleagues say or maybe you even think them yourself. My patient is too old, or too frail or has too many other medical problems to do anything further. And again, that's completely wrong. And here you can see the effect of dapagliflozin compared to placebo according to frailty. And along the x-axis of this slide is a Frailty Index, the higher that index, the more frail patients are. And what you can see is that the hazard ratio is consistently below one, in other words, demonstrating benefit of an SGLT2 inhibitor and that's true, even in the most frail patients. So these drugs that we're talking about today are beneficial, even in frail, elderly, morbid patients. And in fact, if you look at quality of life, which may be the most important thing for these older frailer patients, you can see that actually the greatest benefit from SGLT2 inhibition is in the patients who are most frail at baseline.

So the last thing just to briefly touch on, but I'm not going to go through in detail, is that of course there are other challenges and barriers related to the healthcare system. And one of them is the fragmented follow-up, that patients often receive, concerns about monitoring patients during follow-up.

And again all of these concerns emphasize the difference between SGLT2 inhibitors and other therapies. There is no need for dose titration. I've already explained that monitoring needs to be minimal. Maybe one check of kidney function, and all the other benefits of these treatments are obtained along with outstanding tolerability.

Thank you very much.

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