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Circulation on the Run

Nov 2, 2020

This week’s episode features author Karolina Szummer and Associate Editor Emmanouil Brilakis as they discuss the article "Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry."


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, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature article, we're going to investigate antiplatelet therapy use, but in older patients, as opposed to those that are middle-aged, and have sustained a prior acute myocardial infarction. But, before we get to that, how about we grab a cup of coffee and jump into the other papers in the issue?

Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here, and I really want to start with a paper that adds to our understanding of, guess what, the sodium=glucose cotransporter 2 inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic effects in combination with loop diuretics. Of course, a clinically really important question since now we know that SGLT2 inhibitors improve outcomes in patients with heart failure in whom they are likely to be co-prescribed with a loop diuretic. So, Professor Chim Lang from University of Dundee and his colleagues performed the RECEDE-CHF trial, which was a randomized double-blind placebo-controlled crossover trial of 23 patients with type 2 diabetes and HF REF taking regular loop diuretics who were randomized to the SGLT2 inhibitor empagliflozin 25 milligrams once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urine volume from baseline at week 6.

Dr Greg Hundley: So, empa versus placebo. What did they find?

Dr Carolyn Lam: In patients with heart failure and type 2 diabetes taking a regular loop diuretic, empagliflozin caused a significant increase in urine volume at both day 3 and week 6, compared to placebo, as well as empa also caused a significant increase in electrolyte-free water clearance. Though there was a small non-significant increase in natural uresis with empagliflozin at day 3, this was absent by week 6. These results suggest that empagliflozin may have an advantageous diabetic profile in patients with type 2 diabetes and heart failure in addition to loop diuretics, with only a short transient natriuresis.

Dr Greg Hundley: Very nice, Carolyn. Great information. Diuretics, heart failure reduced ejection fraction, and empagliflozin. Well, my clinical paper comes from Dr Renato Lopes from Duke University Medical Center, and this is a sub study from the ISCHEMIA trial that evaluates whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure or left ventricular dysfunction when the EF is greater than 35%, but less than 45%.

Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite topic. So, Greg, what did they find?

Dr Greg Hundley: Those with heart failure and left ventricular dysfunction randomized to the invasive versus the conservative strategy had a lower rate of the primary outcome, 17% versus 29%. Whereas those without heart failure and left ventricular dysfunction did not, 13% versus 14%. A similar differential effect was seen for the primary outcome, all-cause mortality and cardiovascular mortality, when invasive versus conservative strategy associated outcomes were analyzed with LVF as a continuous variable for those with and without prior heart failure.

Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can you summarize our take home message?

Dr Greg Hundley: Well, Carolyn, ischemia trial participants with stable ischemic heart disease and at least moderate ischemia with a history of heart failure or LV dysfunction, were at increased risk for the primary outcome. And in this small high-risk subgroup with heart failure and an ETF between 35% and 45%, an initial invasive approach was associated with a better event free survival. This result should really be considered for hypothesis generation and future studies.

Dr Carolyn Lam: Greg, for the next paper, do you remember hydrogen sulfide? The stuff we learned about in school. It's the gas with that characteristic foul odor of rotten eggs. Well, guess what? This whole paper is about hydrogen sulfide, and in the body, it actually has antihypertensive and anti-inflammatory effects, and its endogenous generation key enzyme is cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T cells. So today's paper provides insights into how all of these players work together in the development of hypertension.
To investigate the pathophysiological relevance of this CSE hydrogen sulfide system, co-corresponding authors, Doctors Geng and Cai from Fuwai hospital and Chinese Academy of Medical Sciences, Peking University Medical College, as well as Dr Xu from Peking University Health Science Center in Beijing. Well, they and their coauthors performed elegant experiments involving peripheral blood lymphocytes, isolated from hypertensive patients or spontaneously hypertensive rats. They also looked at mice with CSE-specific knockout in T cells, and CD4 null mice.

Dr Greg Hundley: Well, Carolyn, what did they find?

Dr Carolyn Lam: Well, they found that endogenous cystathionine gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine beta-synthase, in lymphocytes, responded to blood pressure changes. Deleting CSE in CD4+ T cells exacerbated
angiotensin II-induced hypertension by reducing circulatory and renal T regulatory numbers. Hydrogen sulfide from CSE self-hydrates, liver kinase 1, thereby activating the AMP kinase energy pathway to promote TReg differentiation and proliferation, which then attenuates the vascular and renal immune inflammation, and thus, prevents hypertension.

Dr Greg Hundley: Carolyn, this sounds like a very thorough study. What are the clinical implications?

Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes may be both a potential biomarker of hypertension, or its complications, or hydrogen sulfide donor may be a therapeutic approach to lower hypertension.

Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from Professor Goo Taeg Oh from Ewha Women's University, and it really involves the world of inflammation. So Carolyn, as you know, macrophages produce many inflammation-associated molecules released by matrix metalloproteinases, such as adhesion molecules, as well as cytokines, which play a crucial role in atherosclerosis. In this paper, the authors investigated the relationship between Ninjurin-1, or nerve injury-induced protein 1, a novel MMP9 substrate expression, and atherosclerosis progression.

Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the results?

Dr Greg Hundley: Well, Carolyn, Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls, as well as athero-prone, apolipoprotein E-deficient, or APOE -/- wild type mice. Two important findings, Carolyn.
First, the authors in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted pro-inflammatory gene expression by activating mitogene-activated protein kinase, or MAP kinase, and inhibiting the phosphoinositide 3-kinase signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increase monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Now, in addition and secondly, macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed both in vitro and in vivo.
Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of the disorder in mice, regardless of the presence of Ninj1.
So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis.

Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank you. Let's go through what else there is in today's issue. In cardiology news, Bridget Kuhn talks about how the pandemic intensifies the push for home-based cardiac rehabilitation options. There's a white paper by Dr Ho and colleagues, including me, describing the diagnostic dilemma of HFpEF. There's a Research Letter by Dr Gill talking about the cardiometabolic trait sepsis and severe COVID-19, a Mendelian randomization investigation. There's also a Research Letter by Dr Wu on the atlas of exosomes microRNAs secreted from human iPSC-derived cardiac cell type.

Dr Greg Hundley: Carolyn, this issue is just packed with articles, because I've got five more to tell our listeners about. First, it's a research letter from Professor G. Hovingh, entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot Study. Next, there's an ECG challenge from Dr Jason Gilge relating to AV conduction during atrial flutter. Next, Dr Keith Churchwell has a nice piece related to the importance of those involved in cardiovascular care and participating in their civic duties, including voting. Next, Professor Karthikeyan has nice On My Mind related to overestimation of stroke risk and rheumatic mitral stenosis and the implications for oral anticoagulation. And finally, Carolyn, another research letter, from Dr Pieter van Paassen, entitled, Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19.
Well, Carolyn, how about we get on to our feature discussion and review in older patients, which antiplatelet therapy may be safest?

Dr Carolyn Lam: Let's go!

Dr Greg Hundley: Well, listeners, now we're turning to our feature discussion, and today we'll talk about antiplatelet therapy. And then we have with us, Dr Karolina Szummer from Karolinska Institutet, and our own Associate Editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Welcome to you both, and Karolina, let's start with you. Could you describe for us your hypothesis and some of the background information that led you to perform this study?

Dr Karolina Szummer: Thank you so much for having me here and for sharing the ideas behind our study. Current recommendations recommend that we use high-potent antiplatelet agents for treating myocardial infarctions, and in particular, elderly patients are not included. So we decided to do an observational study to look at patients in our Swedish registries treated for myocardial infarctions who were 80 years and older.
Dr Greg Hundley: Very nice. Can you tell us a little bit more about your study design? And also the study population?

Dr Karolina Szummer: The startup populations are all patients who were admitted to an acute coronary care unit for treatment of myocardial infarctions, and they were all 80 years and older, and they were included from 2010 to 2017. So this encompasses the period during which treatment with ticagrelor was introduced. So we are comparing to ticagrelor versus clopidogrel for the outcomes during the year, following the myocardial infarction.

Dr Greg Hundley: And how many patients did you enroll in the study? And what were your study results?

Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and these consisted of non-STEMI and of STEMI patients. The majority, about two thirds, were non-STEMI patients. We show, in this study, elderly patients have a lower risk of readmission for myocardial infarction or stroke, but they have a higher risk of having readmission for bleeding and death. So the risk-benefit ratio seems to be skewed towards having, probably, more harm with ticagrelor being more risky than clopidogrel in this study population of elderly.

Dr Greg Hundley: And was this true for both men and for women?

Dr Karolina Szummer: Yes. So this was true for both men and women. And we did a sensitivity analysis. We looked closer at those who are younger than 80 years old, and in this patient population, the results selected in the same way as for our cohort of elderly, they actually did have the same benefit with a low risk of MI, stroke, and death, and high risk of bleeding. But in the elderly, we noticed a signal towards harm with an increased risk of death.

Dr Greg Hundley: It sounds like with ticagrelor, did we have a lower risk of death and a slightly lower risk of myocardial infarction and stroke, but a higher risk of bleeding? Was that the findings?

Dr Karolina Szummer: So for the elderly, there was a high-risk of death and bleeding with ticagrelor compared to clopidogrel, but a lower risk of ischemic component of MI and stroke.

Dr Greg Hundley: And then with those under 80, those were the ones that had the lower risk of death, lower risk of MI and stroke, but the higher risk of bleeding?

Dr Karolina Szummer: Yes, that's correct. So really the end point that differs most is that there is sustainment towards higher mortality in the elderly, because in both younger and elderly, the risk of readmission for bleeding was elevated in both.

Dr Greg Hundley: Now, let's turn to our own Associate Editor, Manos Brilakis. Manos, can you help us put these results into perspective, relative to other studies that evaluate the efficacy of antiplatelet therapy, post myocardial infarction?

Dr Emmanouil (Manos) Brilakis: I would like to start by congratulating Dr Szummer. It's a wonderful paper, and, I think, provide some new insights on how to use the medications in the ACS patients. And going on the background, if we look at the guidelines, both the European guidelines, as well as the American guidelines, what they say is that both ticagrelor, as well as prasugrel, are preferred and recommended for patients with ACS, both non-ST elevation ACS, as well as ST segment elevation myocardial infarction. And actually, European guidelines say that clopidogrel should only be used when prasugrel or ticagrelor are not available or are contraindicated. And this is based on two trials.
One is the PLATO trial, and the other is the TRITON-TIMI 38, that both showed, actually, more benefit with the more intensive P2Y12 inhibitors. And this is what is extrapolated to all patient populations. But as you've heard before, there was only a minority of elderly patients that were included in those trials, about 13% to 15%, and that is why the present study is important, because it suggests that maybe we should look more carefully into the patient's age and potentially other characteristics like frailty or other comorbidities, that might actually alter the risk-benefit ratio. And maybe those medications should not be routinely given to all patients, but perhaps, elderly patients, or at least some of them, might not require, and actually be better off with clopidogrel.

Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study was observational. What do you see as, perhaps, a next study to follow up the results that you've brought to us with this study?
Dr Karolina Szummer: So the next step would definitely be to do a randomized control trial in the elderly to explore this topic further, to really know for sure what the safety and efficacy is, and what's the best treatment would be for these patients.

Dr Greg Hundley: Very good. And Manos, do you have anything to add?

Dr Emmanouil (Manos) Brilakis: One more thing. So, there was actually a trial that compared ticagrelor as well as prasugrel with clopidogrel in elderly patients that was called the POPUlar AGE trial that was published last year. And actually this one, published earlier this year, and actually this trial randomized a thousand patients who were more than 70 years old, to either more-intensive or less-intensive. And the results were actually very similar to the findings from Dr Szummer's study from SWEDEHEART, showing that there was more bleeding without any ischemic benefit. And didn't show actually higher mortality but didn't show any significant benefit. So that actually adds to the data that maybe the elderly patients, the selection of antiplatelet agent should be taken into account.
And I think for me, this also extrapolates the high bleed risk, higher risk of bleeding, based on criteria, which we currently use mainly for duration. We say, for example, if you're precise DAPT score, which is a score for determining risk of bleeding, is high, you should consider shorter duration of DAPT, but it doesn't say anything about the type of DAPT. And for me, this makes sense that the high bleeding risk, and age is one of the main risk factors for high bleeding risk, should be taken into account also for determining the type of P2Y12 inhibitor.

Dr Greg Hundley: Well listeners, we've had a great discussion with Karolina Szummer from Karolinska Institutet, and our own Manos Brilakis from the Minneapolis Heart Institute, really reviewing the utility of ticagrelor versus clopidogrel in older individuals, above the age of 80, that have sustained myocardial infarction, and identifying that ticagrelor is associated with a higher risk of death and bleeding, as opposed to clopidogrel, opening the question up as to whether further studies in older individuals need to be performed to examine the efficacy of antiplatelet therapy.
So, on behalf of Carolyn and myself, we wish you a great week and look forward to catching you On the Run next week. This program is copyright the American Heart Association, 2020.