Circulation October 27, 2020 Issue

Oct 26, 2020

This week’s episode includes author John McMurray and Associate Editor Brendan Everett as they discuss the effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction.

TRANSCRIPT BELOW:

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, I hear you might have an interesting feature paper?

Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward to this one, because we cannot get enough of the DAPA-HF study. This is another very important prespecified analysis, looking at the effect of dapagliflozin on outpatient worsening of patients with heart failure with reduced ejection fraction. Very important stuff coming right up, but first, I've got two papers looking at congenital heart disease that I'd like to share with you, Greg. Have you got your coffee?

Dr Greg Hundley: Yeah, I do. Let's get going.

Dr Carolyn Lam: Well, as you know, the mechanisms of congenital heart disease associated right ventricular dysfunction are not well-understood. And so, in this first paper, Dr Reddy from Stanford University and colleagues assessed lipid peroxidation, a potent form of oxidative stress, as well as mitochondrial function and structure, in right ventricular myocardium, collected from patients with and without right ventricular failure.
And what they found, was that right ventricular failure was characterized by increased oxidation of membrane phospholipids, known as lipid peroxidation and its products, such as 4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and mitochondrial proteins, and was associated with decreased myocardial energy generation and mitochondrial structural disruption with increasing severity of right ventricular hypertrophy and right ventricular failure. Mechanistically, the authors showed that 4-HNE was sufficient to decrease energy generation by inhibiting electron transport chain complex activities and mitochondrial dynamics.

Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So clinically, what are the implications?

Dr Carolyn Lam: I thought you'd ask. Well, since standard heart failure therapies, such as ACE inhibitors and beta blockers, are ineffective in the treatment of right ventricular failure, developing therapies focusing on new targets, such as what we talked about, the lipid peroxidation, could improve right ventricular function in
congenital heart diseases by improving mitochondrial energy generation and cardiomyocyte survival.

Dr Greg Hundley: Ah, very interesting, Carolyn.

Dr Carolyn Lam: Thank you. The next paper, also very interesting, this time focusing on Tetralogy of Fallot, the most common cyanotic congenital heart disease. Now, this is from Dr Marijon from Hôpital Européen Georges-Pompidou in France and colleagues who highlighted, first, that sudden cardiac death represents an important mode of death in these patients with Tetralogy of Fallot, yet data evaluating the ICDs in these patient population, really, has remained scarce. And so, they use the nationwide French registry to include 165 patients with Tetralogy of Fallot with an ICD initiated in 2010 by the French Institute of Health and Medical Research. 63%, by the way, of these ICDs, were used for secondary prevention.

Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they find?

Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% overall, 7.1% in the primary prevention, and 12.5% in the secondary prevention cohorts, respectively. 43% of patients presented with at least one ICD complication, and, importantly, QRS fragmentation was the only predictor of appropriate ICD therapies.
So, even before you asked me, Greg, the take home message is, patients with Tetralogy of Fallot and an ICD, experience high rates of appropriate therapies, including those implanted for primary prevention. The considerable long-term burden of ICD-related complication, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria, including QRS fragmentation, might improve our risk prediction.

Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot there. Well, I'm going to steer us to two other papers in the issue, and the first one is from the world of basic science, and it's from Dr John Cooke from the Houston Methodist Research Institute. So Carolyn, the angiogenic response to ischemia restores perfusion, so as to preserve tissue. Something we all know. A role for mesenchymal to endothelial transition in the angiogenic response is controversial, and this study utilized a murine model of hindlimb ischemia and an in vivo Matrigel plug assay, together with lineage tracing studies and single-cell RNA sequencing, to examine the transcriptional and functional changes in fibroblasts in response to ischemia, to determine if resident fibroblasts contribute to angiogenesis.

Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts contribute to angiogenesis? What did they find, can't wait?

Dr Greg Hundley: Yeah, Carolyn. So, in both mice and human-isolated fibroblasts, these author studies indicated the presence of subsets of tissue fibroblasts, which seemed poised to contribute to the angiogenic response. And the expansion of these subsets with ischemia was dependent upon activation of innate immune signaling, and this signaling contributed to recovery of perfusion and preservation of ischemic tissue. Really interesting findings. Didn't suspect the fibroblasts as being the contributors here.

Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another one.

Dr Greg Hundley: Yes. So the next study is from Professor Phillips Tsao from Stanford University School of Medicine. Well, Carolyn, this is a genome-wide association study, and it's from the Million Veteran Program, testing 18 million DNA sequence variants in patients with abdominal aortic aneurysms. In the study, they identified 7,642 cases and 172,172 controls in veterans of European ancestry, with independent replication and another study in 4,009 72 cases and 99,858 controls.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: So it's nice, they have a replication study. The authors then use Mendelian randomization to examine the causal effects of blood pressure on abdominal aortic aneurysms. And they examine the association of abdominal aortic aneurysm risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and lastly, derived a genome-wide polygenic risk score to identify a subset of the population at greater risk for disease.

Dr Carolyn Lam: Wow. So a GWA study with replication to identify those at risk for abdominal aortic aneurysms in huge cohorts. What did they find?

Dr Greg Hundley: Well, Carolyn, this study was managed by one of our experts in GWA studies, Dr Wendy Post, and through GWAs, the authors identified 14 novel loci, and there were already 10, so it brings the total number of significant abdominal aortic aneurysm loci to 24. So a new finding there. And in their Mendelian randomization analysis, they demonstrated that a genetic increase of 10 millimeters of mercury in diastolic blood pressure, as opposed to systolic blood pressure, likely had a causal relationship with the future development of abdominal aortic aneurysms. They observed that 19 of those 24 aortic aneurysm risk variants associate with aneurysms in at least one other vascular territory. And then lastly, a 29 variant polygenic risk score was strongly associated with abdominal aortic aneurysms, independent of family history and smoking risk factors.
So Carolyn, in conclusion, the authors in this study identify novel abdominal aortic aneurysm genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of abdominal aortic aneurysms, independent of their family history. And their data suggests that perhaps extending current screening guidelines to include testing for those with high polygenic abdominal aortic aneurysm risk, would significantly increase the yield of many of our current screening algorithms, as you know, that predominate based on smoking and age.

Dr Carolyn Lam: Wow. Very, very impressive and convincing data. Thanks, Greg. Let me tell you about other papers in today's issues. There's a research letter by Dr Tiburcy on inhibition of prolyl-hydroxylase domain enzymes, and how that protects from reoxygenation injury in the engineered human myocardium. There's another research letter from Dr Ohbe, entitled, The Risk of Cardiovascular Events after a Spouse's ICU Admission. And, one more from Dr Ganatra, on chimeric antigen receptor T cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma.

Dr Greg Hundley: You know, Carolyn, our research letters, they really pack a punch. Such very interesting research, in a nice concise format. I've got some other publications. So first, there's an On My Mind piece from our own Charlie Loewenstein, and also Dr Solomon from Boston, Massachusetts, involving, Severe COVID-19 as a Microvascular Disease, does endothelial exocytosis drive COVID-19? And next, there's a case series entitled, ECMO Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani. And then finally, Carolyn, a very nice ECG challenge from Dr Bansal, related to identifying the location of an AV block. Well, Carolyn, I'm really excited to get onto your feature discussion.

Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks at a prespecified analysis of DAPA-HF. My goodness, I don't think we can get enough of the data from DAPA-HF, and we have none other than be corresponding author, Dr John McMurray from University of Glasgow, to discuss this exciting paper, as well as our associate editor, Dr Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. So John, today's feature paper, all about outpatient worsening of heart failure. Could you please start by defining what we meant by that, and why is it so important?

Dr John McMurray: Our interest in this actually started back when we did PARADIGM and we had collected, in a not very systematic way, information about episodes of outpatient worsening, so by that, I mean episodes of worsening symptoms and signs, not leading the patient to go to the emergency department or be admitted to hospital. The sort of worsening that a patient might tell you about in your outpatient clinic, say they're a bit more breathless or they've got a bit more ankle swelling, and you do something about it. And that's the critical part. You decide to increase their dose of diuretic, add another drug.
And in PARADIGM, we find that those episodes, first of all, were quite common, and secondly, and most importantly, we're actually prognostically very significant. They were associated with worse outcomes. So in that HF, we decided that we would collect these more systematically, we would try and define them a little bit more robustly, so we would require the investigator to report worsening signs and symptoms, and we also wanted evidence that additional treatment had been given and then that had been sustained for at least a month, because, as you know, diuretic dose can increase and decrease.
Then we prespecified, as you said, Carolyn, that we would then incorporate those manifestations of worsening, as an additional component to our primary composite endpoint, which was cardiovascular death, heart failure hospitalization, worsening of heart failure requiring intravenous therapy, so an urgent visit for that, that would often be in an emergency department, and then in addition to that, this further manifestation of worsening as the extra component to this broader composite outcome that we hoped would encompass the whole range of worsening of heart failure that a patient might experience.

Dr Carolyn Lam: Thanks so much, John, and you actually preempted my question of how it differed from the original primary outcome that included urgent heart failure visits, intravenous diuretic use, but not these nuance outpatient intensification of heart failure therapy that I really salute you for prospectively collecting information on. So could you summarize what you found, please?

Dr John McMurray: Well, first comment to make, Carolyn, is that we included those urgent visits requiring intravenous therapy, because, as you know, in the U.S., I think there is a move to try and avoid admission and to treat patients in the ambulatory care setting or non-ward setting. Although, I have to say, as it turned out, those episodes of worsening were very infrequent. There was, I think, 33 in total in DAPA-HF, compared to almost 600 of the other episodes of worsening. The ones that we almost feel at a brainstem reflex level when we see patients in our clinics.
So what did we find? Well, we find that when you add those episodes of worsening, then, of course, you considerably increase the proportion of patients who have, from what you might call, the most trivial manifestation, worsening the events we just talked about, all the way through to the very worst, in other words, death, from cardiovascular causes, in fact, so much so, that by about two years of follow-up, the Kaplan-Meier rate for that expanded composite endpoint was about 33%. And, as you know, Carolyn, we're talking about a trial that enrolled patients who were very well-treated by conventional standards and who, by and large, had mild symptoms, but 70% were NYHA class II. And yet, within two years, if you take into account all of these different manifestations of worsening, we had about one-in-three people in the placebo group that deteriorates, and we reduced the risk of deterioration with dapagliflozin, we reduced the instance of that expanded composite endpoint by 27%, and that was a highly statistically significant result.
And if you like numbers needed to treat, then for that expanded very broad composite endpoint, the number needed to treat over the median follow-up of 18.2 months, was only 16. And by the way, we did confirm that those outpatient worsening events were prognostically significant as well.

Dr Carolyn Lam: Very good. Brendan, could I bring you in on this? It's got such great implications, maybe you could share a little bit about what the editors thought when we saw this paper?

Dr Brendan Everett: One of the key things that the editors thought when they reviewed this, was the fact that, as you pointed out, you collected these outpatient worsening episodes prospectively across the trial and did so in a very rigorous and systematic way. And I think for those of us who take care of patients with heart failure, which of course is most cardiologists, these kinds of episodes where your patient calls you and their weight's gone up, or where they've gotten a little more short of breath, then you, over the phone, intensify their diuretic regimen, are incredibly common, and, of course, bothersome to the patient and challenging for the clinician who's caring for the patients too. So I think, in that sense, it's a really important paper. That was the other aspect, I think, that the editors were interested in. But the impact, the clinical impact on day-to-day care of patients with heart failure, was substantial.
The other part that I found intriguing, because of course, when you're caring for individual patients, you don't have a sense, necessarily, of what these episodes mean in a broader population for those patients' overall risk of bad outcomes. So you mentioned it right at the end when you were speaking a moment ago, about the association of these outpatient intensifications of oral diuretic therapy and their association with future bad outcomes within the trial. Could you tell us a little bit about what those were and why they ended up seeming so important, both to patients and to you as the trialist?

Dr John McMurray: We write about these being common, in fact, in the placebo group in DAPA-HF. I think it was 14% of patients had one of those episodes of outpatient worsening. And again, as you correctly identified, in the majority of cases, the therapeutic intervention by the physician, was simply to increase the dose of diuretic, although, actually about 40% of people also, at some point, had the addition of another drug.
So, in terms of the significance of those events, in PARADIGM, we find that they appeared to be associated with almost the same impact on mortality as being admitted to hospital with worsening heart failure. But in fact, in DAPA-HF, where we collected more of these events, so maybe we collected, perhaps, the more severe cases in DAPA where we collected them systematically, we find that the prognostic impact wasn't quite as large. So for example, if you were admitted to hospital with heart failure during DAPA-HF, then you were six-times more likely, subsequently, to die in that rather short follow-up period, than if you had no manifestation of worsening.
On the other hand, if you had an outpatient episode of worsening, then it was around a three-fold higher risk of death than if you had no manifestation of worsening. So, my take home from this was that these episodes really do matter to patients. Not only, of course, do they matter because it means the patient doesn't feel so good, but they matter because that patient suddenly is on a different prognostic trajectory, and you can change that by intervening.
So these events are common, they're prognostically bad news, and fortunately, we can reduce them. And maybe the last thing to say, which I also didn't mention, I apologize, was that, of course, if you look at that expanded endpoint, as you can imagine, because there's so many events now, you see the effect of treatment very, very quickly. So by day 27 after randomization, in other words, by day 27 after starting dapagliflozin, we had a statistically significant reduction in the occurrence of that comp standpoint, that then remained significant thereafter.

Dr Brendan Everett: Thanks, John. I had one other question that I hope doesn't take us too far into the weeds, but I think as a clinician, when you care for these patients, you try to intensify their outpatient therapy, and when that seems to fail, the patient then becomes admitted to the hospital. And I thought it was very interesting and thoughtful the way that you approach that problem, in other words, you have potentially, of this composite endpoint, you have the outpatient worsening that comes first, and then it's followed, in many cases, by a hospitalization for heart failure. How did you tease those two apart? And what analyses did you do to make sure that what you were really measuring was the effect of the outpatient intensification, rather than really just a prelude to a hospital?

Dr John McMurray: Very good question, Brendan. So, obviously, we were concerned about the possibility of double counting, so we did a primary analysis in which we built in a blanking window. So, for example, if you had an episode about outpatient and you or I increased the patient's oral therapy, but within 30 days, they were admitted to the hospital, then in our analysis, that patient only counted once, and the event that counted was the hospital admission, not the outpatient episode of worsening.
And then, as I said, we did a number of sensitivity analyses where we adjusted the length of that blanking period, because we recognized, obviously, that some people, that episode of outpatient worsening that you intervene for, your intervention may not work and they may still get hospitalized. So we try to, as you obviously identified when you read our manuscript, we tried to counter that by not double counting episodes of outpatient worsening that were closely adjacent to the hospital admission.

Dr Carolyn Lam: Could I end with just one quick question? You've published many times with us at Circulation, and I'd like to think that that's from a very good experience with us, with working with us, and I've noticed even in this discussion, it's just so interesting the exchange. And so, John, could you say a few words about publishing in Circulation, and why do it?

Dr John McMurray: Well, obviously it's our leading cardiovascular journal. As I was being trained as a fellow, it was every fellow's aspiration to publish a paper in Circulation. So reputationally, obviously, it's very, very important.
But why do I like Circulation other than that? Well, first of all, you handle papers quickly and efficiently. I think you're very fair. I really like the reviews. So I would say one of the greatest frustrations most authors, and certainly I know that from my own experience, is when you get poor reviews. I don't think I get those from
Circulation, so you obviously have a much higher quality review. I like the way the editors give you guidance about the manuscript and how to respond to the reviewers. That's really, really helpful, because sometimes you think, "Well, that reviewer’s comment doesn't make sense. Do I have to really do that?" But often, your replies to me, come with guidance about how to handle the different reviewers’ comments. So, all in all, it's fair. I would say that's always important. Everybody will not get every paper accepted, but I think you get a very fair response from Circulation. It's good. It's thoughtful. So, that's fine.

Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on behalf of Brendan as well, and kudos to him because obviously he managed this paper so well. Thank you, audience, for joining us today on Circulation on the Run. So don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association.