EMPORER-Preserved: Interview with Prof. Stefan Anker

Medicom: Thank you so much for joining us, Professor Anker. Can you tell me a little bit about the significance of the results presented at the European Society of Cardiology with regard to the EMPEROR-Preserved trial?

Prof. Anker: Thank you so much for the question about EMPEROR-Preserved, which is the first positive trial with clinical trial results that are really meaningful for patients in heart failure with preserved ejection fraction. Now we all know that SGLT2 inhibitors work in heart failure with reduced ejection fraction, less than 20%, which has been reported over the last one or two years from several trials. Now, we are focusing on heart failure with preserved ejection fraction, where the current guidelines and new guidelines actually do not recommend any specific therapy because simply the trials done in this field more or less narrowly missed their target of achieving significance.

With  EMPEROR-Preserved, recruiting 6,000 patients over the last 3 and a half years and following them for 26 months on average, we are looking at empagliflozin 10 mg once daily versus placebo. And for the first time, we are now able to report that there is a 21% reduction in the primary endpoint of cardiovascular mortality and heart failure hospitalisation with a P-value of 0.0003.

These results clearly are meaningful and important for these patients and hopefully in the future lead to a standardisation of therapy, also in the heart failure with preserved ejection fraction field. Looking a little bit in more detail into the results, they are driven by heart failure hospitalisation reductions. If you look at the first and recurrent heart failure hospitalisation, which was the key secondary endpoint of the study, you have a 27% reduction with a p-value of 0.001, again a meaningful result. The second component of the primary endpoint, cardiovascular mortality was reduced nominally by 9%, not achieving significance, but contributing overall to the primary endpoint, of course.

If you look at the secondary endpoint, that is the change in the eGFR slope. And remember, in EMPEROR-Reduced, we had basically a positive impact on the eGFR slope and also a reduction in renal events. Here we also have an impact on the eGFR slope, highly significant over time, but unfortunately not impacting, perhaps due to too short a follow-up, or maybe because of issues with the definition of how we look at these events, not achieving a difference in the renal event outcomes.

Overall, we are basically seeing a trial where heart failure, hospitalisation, and cardiovascular death are reduced and, importantly, the quality of life measures and symptomatic status are also significantly improved. All-around, this study tells us that you can use this drug and it is actually very safe.

Medicom: were there new safety signals?

Prof. Anker: Thank you for asking this question. There was nothing new with regards to safety signal that gives you any concern. Indeed, ketoacidosis was 4 versus 5 events in the 3000 patients, respectively in the two treatment arms. And of course, as expected genital tract infections were somewhat increased, 2.2% versus 0.7%.

This means that we need to continue the efforts for hygiene advice and need to continue basically make patients aware. There was a small increase of hypotension,10.4% versus 8.6% on placebo. The last thing I would like to say, if you look at all-cause mortality, it is neutral on all-cause mortality with a hazard ratio of 1.00.

Medicom: will there be any sub-analyses coming up that we can look forward to? What are the next steps?  

Prof Anker: The next steps are many-fold, and at the ESC 2021 meeting there will be several presentations on the EMPEROR program. So this main result is coming out in the New England Journal of Medicine, but we have additional results reported comparing and contrasting the results, by ejection fraction for instance, and contrasting them to the PARAGON  trial results, but also getting some more granularity for some of the results. How quickly the benefits are seen, for instance, they are seen after 18 days already with significance. And so all of this is published as soon as we can.

But then future studies on quality of life, on a true HFpEF , focusing on those with 50% and above. Let me emphasise one thing from the primary endpoint results analysis, there is no interaction for the primary endpoint, for ejection fraction, for gender, or also for any other important thing, for instance, diabetes. For all the key subgroups, no difference at all. If you start to look into the secondary endpoints, the situation is a little bit different. You will see that ejection fraction maybe plays a role on the kidney outcomes and on heart failure hospitalisation. But I do not think that is a big surprise.

But overall this is a rich source for further study and we shall indeed report on that.

Medicom: Could you just zoom in on the blood pressure results, please?  

Prof. Anker: So while the average change in blood pressure is actually one-millimeter mercury reduction with empagliflozin, and that is significant, but not really dramatic at all to explain the results.

The body weight changes with a 1.3 kilogram reduction with empagliflozin, and is almost neutral over time on the placebo group. That is significant, but again, it is small. The biggest change in terms of these kinds of vital signs on biomarker results was actually on the hematorit, with 2.4% change, highly, highly significant. But maybe that is a sign that these patients get more stable and then stay out of hospitals.

You could say that the new guidelines are already out of date.

 

Read more on the EMPEROR-Preserved trial outcomes in our article Empagliflozin: First drug with clear benefit in HFpEF patients.

 

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Posted on 30 August 202127 October 2021