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Circulation on the Run: September 26, 2003

  • Carolyn S.P. Lam, MBBS, PhD orcid
  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20230925.181139

Dr. Greg Hundley:

Welcome, listeners, to this September 26th issue of Circulation on the Run. And I am one of your co-hosts, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital in University of Oslo in Norway.

Dr. Greg Hundley:

Peder, oh my goodness, the feature discussion today, a very provocative feature discussion. We have been discussing over the past two years, really the impact of SGLT2 inhibition and preventing heart failure, all kinds of things. And of course, this is one of Carolyn's favorite topics. Well, this feature discussion today by Milton Packer is going to investigate the effects of withdrawing empagliflozin in patients with heart failure. So really looking at the long-term effects of patients that have been initiated on an SGLT2 inhibitor and then having that withdrawn. Very exciting. But before we get to that feature discussion, how about we grab a cup of coffee and we work through some of the other articles in the issue? And this week, we have several articles to discuss in this summary. And how about if I go first?

Dr. Peder Myhre:

I'm ready with my coffee to listen, Greg, so go ahead.

Dr. Greg Hundley:

Thanks Peder. So Peder, the short-term incidents of ischemic stroke after a transient ischemic attack or TIA is actually very high. However, data on the long-term incidents are not well known and they are needed to guide prevented strategies. So these authors in collaboration with corresponding author, Dr. Naja Vinding from Copenhagen University Hospital evaluated patients with a first-time TIA at the index date in the Danish Stroke Registry. And they evaluated individuals from the time period of January, 2014 through December of 2020, and they matched them in a one to four ratio with persons from the background population, and then also in a one to one ratio with patients with a first-time ischemic stroke. And both of these matching initiatives were based on age, sex, and calendar year. And then they followed the incidences of ischemic stroke and mortality from the index date of where they entered the study.

Dr. Peder Myhre:

Oh wow. Those Danish registries, we learned so much from them. And Greg, what did they find in this study with respect to ischemic stroke following a TIA?

Dr. Greg Hundley:

Right, Peder. So first of all, the team included 21,500 patients with a TIA, 86,000 patients from the background population. Remember that was the one to four match. And then another 21,500 patients with ischemic stroke. And the median age across all was 70 years, and 53% were men. So findings, patients with TIA had more comorbidities than the background population, yet less than the control stroke population. The five-year incidence of ischemic stroke following TIA was 6.1% and that was higher than for the background population, which was 1.5%, but it was lower than the control stroke population, which was 8.9%. So 6.1, TIA, 1.5 for background population, and then 8.9 for the stroke population. Then the five-year mortality for patients with TIA was 18.6%, which was higher than the background population of 14.8%, but was lower than the control stroke population, which was elevated at 30.1%.

Dr. Peder Myhre:

Oh wow. That is really impressive findings. And Greg, what would you say is the take home message from this paper?

Dr. Greg Hundley:

Right, Peder. So it appears that patients with first-time TIA had an incidence of ischemic stroke of 6.1% during the five-year follow-up period. Following adjustment for relevant comorbidities, this incidence was approximately fivefold higher than what one would find for controls that had not experienced TIA or a stroke previously, but was 40% lower than patients that had previously or had experienced a prior ischemic stroke.

Dr. Peder Myhre:

Oh, beautiful summary, Greg. Thank you. And now Greg, we are going into preclinical science, and this first paper is about cyclic GMP-AMP synthase, which responds to pathogenic DNA derived from bacteria and viruses. So this is in the field of sepsis and cardiovascular complications of sepsis. And once this activation occurs upon DNA binding this synthase, cGAS generates the second messenger cyclic GMP-AMP, leading to induction of genes associated with the innate immune response. And activation of this pathway plays an important role in cardiovascular disease and has been implicated in myocardial ischemic injury, the development of heart failure, cardiac dysfunction during sepsis, and diabetic cardiomyopathy. So in this study, Greg, which comes to us from Joseph Burgoyne from Kings College, London, the investigators analyzed whether this pathway could play a role in the crosstalk between inflammation and blood pressure regulation.

Dr. Greg Hundley:

Well, Peder, really interesting. It sounds like you're describing a potential mechanism mediating hypertension and tissue hypoperfusion during sepsis. So that's a fascinating topic. What did they find?

Dr. Peder Myhre:

Indeed, Greg. And these authors made several interesting findings. First, this synthase cGAS can mediate lowering of blood pressure through direct cGAMP dependent protein kinase one activation. Second, cGAS within the vascular endothelium generates cGAMP that is actively extruded by a protein called MRP1, and then imported into neighboring vascular smooth muscle cells through the volume regulated anion channel. And third, Greg, the activation of this pathway plays a key role during sepsis by mediating hypertension and tissue hypoperfusion. So in summary, these findings provide novel insights into the pathological processes that underlie sepsis, and targeting processes that mediate the [inaudible 00:07:11] formation or transport of cGAMP, may provide new therapeutics to treat sepsis.

Dr. Greg Hundley:

Beautifully described, and a new preclinical science study reflecting information pertaining to the development of sepsis. Well, Peder, the next paper here takes us back to the world of clinical science. And as you know, limited information is available on the comparative efficacy and safety of different stent platforms in patients at high bleeding risks undergoing an abbreviated dual antiplatelet therapy duration after PCI. So the aim of the Bioflow-DAPT study, which was an international randomized open-label trial, conducted at 52 interventional cardiology hospitals in 18 countries, from February, 2020 through September, 2021, was to compare the safety and effectiveness of the biodegradable polymer sirolimus-eluting stent with the durable polymer zotarolimus-eluting stent in patients at high bleeding risk receiving one month of dual antiplatelet therapy after PCI.

Dr. Peder Myhre:

Interesting, Greg. So who did they include in this study and what was the proposed outcomes?

Dr. Greg Hundley:

Right, Peder. So they included patients with a clinical indication to PCI because of acute or chronic coronary syndrome who fulfilled one or more criteria for high bleeding risk. Patients were randomized to receive either biodegradable polymer sirolimus-eluting stents or durable polymer slow release zotarolimus-eluting stents after successful lesion preparation followed by one month of dual antiplatelet therapy, and thereafter, single antiplatelet therapy. And the primary outcome was the composite of death from cardiac causes, myocardial infarction, or stent thrombosis at one year, and was powered for non-inferiority with an absolute margin of 4.1% at one-sided, 5% alpha.

Dr. Peder Myhre:

Oh, great. So now you got me on the edge of the seat, Greg. What did they find?

Dr. Greg Hundley:

Right, Peder. So they enrolled a total of 1,948 patients at high bleeding risk, and randomly assigned one to one to receive the two different stents. So they had 969 individuals in sirolimus-eluting stents and then 979 in zotarolimus-eluting stents. And at one year the primary outcome was observed in 33 of 969 patients, so 3.6% in the biodegradable sirolimus-eluting stent group, and 32 of 979 or 3.4% in the durable polymer zotarolimus-eluting stent group. So the risk difference was only 0.2 percentage points with a P value of 0.0001, three zeros and a one, for non-inferiority for both tests.

And so, Peder, in conclusion, among patients at high risk for bleeding who received one month of dual antiplatelet therapy after PCI, the use of biodegradable polymer sirolimus-eluting stents was non-inferior to the use of durable polymer zotarolimus-eluting stents with regard to the composite of death from cardiac causes, myocardial infarction or stent thrombosis. And so therefore, Peder, in patients at high bleeding risk who are meant to receive one month of dual antiplatelet therapy after PCI, the use of biodegradable polymer sirolimus-eluting stent is a reasonable alternative to the use of the durable polymer zotarolimus-eluting stent at the time of their percutaneous intervention.

Dr. Peder Myhre:

Excellent. Greg, thank you for summarizing that. And we have some other papers in this issue. We have a perspective piece by Dr. Sarah Godfrey and titled Expanding the Paradigm for Cardiovascular Palliative Care. And we have our own Bridget Kuhn with Cardiology News where she digs into the reprieve study, which was recently published in New England Journal of Medicine. And the title is Statin Reduces Heart Risk in Patients with HIV.

Dr. Greg Hundley:

Great, Peder. Well, there's also in the mailbag, an exchange of letters between Doctors Aldana Bitar, Professor Jiyang, and also Professor Perez de Esla regarding the paper Alirocumab and coronary atherosclerosis in asymptomatic patients with familial hypercholesterolemia, The Architect Study. Well Peder, how about now we jump to that feature discussion and evaluate the impact of withdrawal of long-term empagliflozin in patients with heart failure.

Dr. Peder Myhre:

I'm so excited. Let's go.

Dr. Greg Hundley:

Well, listeners now we're on to our feature discussion on this September 26th, and we have with us today Dr. Milton Packer from the Baylor Heart and Vascular Institute in Dallas, Texas, and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. Welcome to you both, gentlemen. Well, Milton, can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you sought to address?

Speaker 3:

Well, we have four foundational drugs for heart failure with a reduced ejection fraction. And we tell patients that they need to take these drugs forever, indefinitely, but we have almost no data that any of these actually continue to work after patients have been taking them for years. When you look at the Kaplan-Meier curves and you see continued separation, that does not mean persistence of a drug effect. And particularly with SGLT2 inhibitors, we know there's a short-term diuretic effect, and that tolerance develops to it because of counter-regulatory mechanisms. So we wanted to know if SGLT2 inhibitors, when given to heart failure, had a persistent effect after patients had taken them for years and years.

Dr. Greg Hundley:

Very nice. And so Milton, to investigate this further, what study design did you use and who did you include? Who was your study population?

Dr. Milton Packer:

Well, we took all the patients who were in EMPEROR-Reduced, that's empagliflozin with reduced ejection fraction, and EMPEROR-Preserved, that's empagliflozin and preserved ejection fraction, two trials of about 9,700 patients. And at the end of the trials, those who had survived and were continued to be taking their study medications were withdrawn from their study drug for about 30 days. And that meant that half of the patients were being withdrawn from empagliflozin and half were being withdrawn from placebo. And this withdrawal period was protocol mandated, very, very important. If you just see what happens when patients are taken off a drug for clinical reasons, that's a biased observation because you don't know if they're getting sick because of the withdrawal of the drug or because of the reason that they withdrew the drug.

Dr. Greg Hundley:

And just remind us quickly, how long had they been on study drug before they were withdrawn for the 30-day period?

Dr. Milton Packer:

In the EMPEROR-Reduced about 16, 17 months, and in EMPEROR-Preserved about 26 months. So on average, about one to three years.

Dr. Greg Hundley:

Perfect. And so can you describe for us then, Milton, what were your study results?

Dr. Milton Packer:

Well, when they were all together at the end of both trials, there were about 7,000 patients, half of them on placebo, half of them on empagliflozin. And they were withdrawn for 30 days. And when patients were withdrawn from placebo, nothing happened. And that's exactly what you would expect, they're being withdrawn from nothing. When patients were withdrawn from empagliflozin, we found a fascinating result. We found that their quality of life measured by Kansas City Cardiomyopathy Questionnaire, health status deteriorated when withdrawn from empagliflozin, and the risk of cardiac events, heart failure events, worsened, increased, when withdrawn from empagliflozin. This occurred within 30 days of withdrawal of the drug. And these were mirror images of what we had seen during the first four to 12 weeks when the drug had been initiated one to three years earlier.

In addition, we measured biochemistry, lab results, vital signs, physiological measurements, and specifically focused on those that reflected inhibition of SGLT2 and sodium hydrogen exchanger three in the proximal tubule. And when we withdrew empagliflozin, we found evidence that the fasting glucose went up, that serum bicarbonate went up, that EGFR, glomerular filtration rate went up, that body weight went up. All were evidence that the patients had stopped experiencing glycosuria and the loss of bicarbonate in the urine, indicative of the tubular action of empagliflozin. So these were striking effects. And our conclusion was that tolerance didn't develop the empagliflozin, either clinically or physiologically, biochemically, even after patients were taking the drug for one, two, three years.

Dr. Greg Hundley:

Wonderful. And just one point of clarification, Milt, in that 30-day period, you mentioned heart failure events, what were those? What did precipitously rise?

Dr. Milton Packer:

Heart failure events, we defined as the primary endpoint in the trial, which was cardiovascular death and heart failure, hospitalizations. And remember that during randomized therapy, benefit of empagliflozin was primary on heart failure hospitalizations. And when we withdrew empagliflozin, the primary deterioration was an increase in heart failure hospitalization.

Dr. Greg Hundley:

Wow. And just very abruptly. So listeners, now we're going to turn to our associate editor, Dr. Brendan Everett from Brigham and Women's Hospital. And Brendan, again as an associate editor at Circulation, you have many papers that come across your desk. What attracted you specifically to this particular study? And then secondly, how might you put some of the results shared by Milton really in the context with what we know about the ongoing investigations related to SGLT2 inhibition?

Dr. Brendan Everett:

Thanks, Greg. And I just want to say that Milt's paper was really, we see a lot of papers and there's some that stick out. And this was one that definitely intrigued me. And I think the primary reason for that is the reasons that he outlined. There's huge numbers of patients who are on multiple therapies, particularly for heart failure. And recently, SGLT2 inhibitors have been added as one of the key foundational medications for, particularly heart failure with reduced ejection fraction, but also now heart failure with preserved ejection fraction. And there's always a question in the clinic as to whether or not how long we need to continue these, especially if the patients recover and feel better or don't have any hospitalizations for an extended period of time. And each of the medicines is associated with some degree of side effects. And in the case of SGLT2 inhibitors often cost as well.

And so there's always sort of, "Do we have to continue these in how long?" So there's not really a good understanding for any of the medicines that we use, it's about what happens if we withdraw it, and do we get away with it, do we not get away with it? We may get away with it in one patient and not in another. And so I think the real intriguing aspect of this was exactly what Milt described, so a protocolized withdrawal of a medication that was assigned randomly. Now we were, well, after the initial randomization, so sometimes there can be some bias introduced during the subsequent, as he said, 16 months in reduced in 26 months or so on average on therapy if preserved. But there were a lot of data in the paper that suggested that even at the time of withdrawal, at the end of the study, the groups on active and placebo were still very well balanced and that there was unlikely to be a significant source of confounding there.

Perhaps not a true randomized trial at that point, but very close to it, I think, is fair to say. And what we saw exactly, we were intrigued by both the biochemical markers that Milt described. Because, I think it's fair to say, and maybe Milt will disagree with me, but the effect of SGLT2 inhibitors on heart failure has been one of the most profound and important changes in this space in the past decade. It's really remarkable. And I don't think we really understand why they're as effective as they are. And you could say, "Well, it's just the diuretic effect of the glucose urine [inaudible 00:21:53]. And I think it's pretty clear that that's probably not at all that it is. And so I think there's a lot of interest in the field and trying to tease out what precisely is happening and why the medications are so effective among patients who are not diabetic.

Right? It's really intriguing. And so this allowed us some insights, and A, they're still working at the close of the trial. When you remove them, it has important physiologic effects and biologic effects. And then three, in an intriguing way, there seems to be an increased risk of hard cardiovascular outcomes. There were, I think about, I want to say 50,49 events in the empagliflozin arm and 40 in the others. So it's not a huge sample size of events, but it is nonetheless persuasive and the best evidence that we have so far that continuing the therapy in the population such as those enrolled in these two randomized trials can continue to be helpful for those patients, both in terms of how they feel and whether or not they're able to stay out of the hospital. And then other important physiologic parameters that suggests that there's ongoing effects of the medicine on the system, on the body.

Dr. Greg Hundley:

Beautifully stated, Brendan, and really gives us almost a lead in, Milt, as a forward thinker in heart failure, both diagnosis and then management. For our listeners, what practical considerations would you suggest that pertain really to the results of this study?

Dr. Milton Packer:

Well, we always think about whether if we give these drugs long-term to patients with heart failure, that we permanently remodel the heart, and the drugs aren't needed anymore. And that's a wish without data. The reality is that if patients typically get their prescriptions monthly and if they miss a month of SGLT2 inhibitors, they are at major risk of heart failure events and worsening symptoms. And we would never have thought that such a deterioration would've occurred so quickly. And it highlights the fact we don't have these data with any of the other foundational drugs. We don't have them with our needs, Beta blockers, MRAs. I'm not suggesting that we need them to continue long-term therapy. And in fact, a randomized trial of withdrawal of these drugs, many people would be very hesitant to do that. But when these patients are taking these drugs to reduce morbidity, mortality, and we say indefinitely, we really mean it, we really mean that they really shouldn't stop therapy even for a month.

Dr. Greg Hundley:

And Milton, just a quick follow up question. I remember we had in this study, patients with both reduced and preserved ejection fraction. Did you find the occurrence of events in that 30-day withdrawal period equally distributed among both groups of those?

Dr. Milton Packer:

Yeah, there was no difference in the withdrawal response between reduced and preserved. I should mention that a larger proportion of patient with preserved were in the trial, largely because when we closed out EMPEROR-Reduced, we did so during the COVID epidemic, and our data were less complete for that trial than for EMPEROR-Preserve.

Dr. Greg Hundley:

Beautifully stated. And Brendan, do you have anything to add?

Dr. Brendan Everett:

I think it's a really intriguing paper, and as Milton pointed out, I think it suggests that there are real downsides to stopping these medications. And oftentimes patients and physicians don't stop them because they want to, but rather because, for one reason or another, they're forced to, whether it's a side effect or, in many of my patients, it's a question of cost and picking and choosing which medications they can actually afford. Particularly those on Medicare where they fall into the donut hole, as we say. I have the good fortune to be involved and be the PI of a study, a comparative effectiveness study, comparing these drugs with some others. I think there's new momentum to consider GLP1 receptor agonists and their effects in this group of patients, particularly heart failure with preserved ejection fraction, I think. And our tendency as docs is to say that, "This drug has a benefit, this drug as a benefit, this drug as a benefit. So you should be on all of them."

And whether or not that ends up really being the case because of overlapping benefits, but also potential toxicities, and then of course the cost of them, both to the patients and to the system, is overall without necessarily an inferred or implied benefit, without a really demonstrated one is an important area. I think, particularly in heart failure, where we are lucky to have some new therapies that appear to be effective, but which are expensive. And I find myself, clinically, often having to choose which ones to use and trying to come up with a rationale, which is sort of back of the envelope rather than driven by data, if you know what I mean.

Dr. Greg Hundley:

Beautiful. Well, listeners, we want to thank Dr. Milton Packer from Baylor Heart and Vascular Institute in Dallas, Texas, and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, for really bringing us these very interesting study results demonstrating a persistent effect of empagliflozin in patients with heart failure, with both reduced and preserved ejection fraction even after years of treatment, which dissipates rapidly within 30 days after withdrawal of that particular drug. Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on The Run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

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