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Circulation on the Run

Jul 6, 2020

Dr Carolyn Lam: Well, the 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 Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature involves the Compass trial, and we'll be talking about a comparison of low-dose rivaroxaban plus aspirin compared to aspirin alone in patients with chronic vascular disease. But before we get to that, how about if we break away and discuss a few other papers. And I'll go first this time, because this week we're going to introduce another new feature in addition to Carolyn's Quiz.

Dr Carolyn Lam: Wait a minute. This was not on the script. What's going on, Greg?

Dr Greg Hundley: It's on the script!

Carolyn, let me get to my first paper. It's from Professor Junling Liu from Shanghai Jiao Tong University School of Medicine, and it involves branched-chain amino acid catabolism and how that may promote thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.

But first, we've got a new feature to add to Carolyn's Quiz. It's called Way or No Way.

Dr Carolyn Lam: Just so everybody knows. This was a one-way decision to add this new component of Carolyn's Quiz, but okay, I'm all for it. Go, Greg!

Dr Greg Hundley: Okay. All right. It's a fast, quick question where our listeners seek your guidance regarding an important scientific discovery from one of our published manuscripts. Are you ready?

Dr Carolyn Lam: No.

Dr Greg Hundley: Okay. Here's your question. Do branched-chain amino acids promote arterial thrombosis. Way or no way?

Dr Carolyn Lam: Maybe?

Dr Greg Hundley: Okay, Carolyn.

Dr Carolyn Lam: I have a feeling you're going to tell us yes, although I wouldn't have guessed that straight away.

Dr Greg Hundley: Okay. Remember that branched-chain amino acids are essential nutrients, including leucine, isoleucine, and valine, and they serve as a resource for energy production and the regulator of important nutrient and metabolic signals.

In this study, the activity of human platelets from healthy subjects before and after ingestion of branched-chain amino acids were measured. PP2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation.

Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no way?

Dr Greg Hundley: Ingestion of branched-chain amino acids significantly enhanced the activity of platelets in response to agonists and increased the risk of arterial thrombosis. The branched-chain amino acid catabolic pathway-driven propionylation of tropomodulin-3 at K255 was found to be an important mechanism underlying the branched-chain amino acid-facilitated platelet activation, and elevated levels of branched-chain amino acids and enhanced expression of positive regulators of branched-chain amino acid catabolism in platelets were found probably responsible for the high platelet activity in type 2 diabetes mellitus.

Dr Carolyn Lam: Very interesting. So yes, it is possible. And what is the clinical implications?

Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or their catabolites, enhance the risk of arterial thrombosis in small animals, and perhaps future human subject studies, that restrict branched-chain amino acid intake or target branched-chain amino acid catabolism may serve as a novel strategy for anti-thrombosis therapy.

Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question for me. Have you heard of Home Time?


Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time out for our kids, but we've been having a lot of Home Time in this COVID-19 with our families.

Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you know it is a patient-centered outcome measure that accounts for rehospitalization mortality and post-discharge care? In the paper I want to talk about, Dr Pandey from UT Southwestern and colleagues aim to characterize risk-adjusted 30-day Home Time in patients with acute myocardial infarction as a hospital-level performance metric, and to evaluate associations with risk-standardized readmission rates. The study included almost 985,000 patients with AMI hospitalization across almost 2,400 hospitals between 2009 and 2015 derived from a hundred percent of Medicare claims data. And they found that 30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varied across hospitals, was associated with post-discharge readmission and mortality outcomes, and meaningfully reclassified hospital performance compared with the 30-day readmission and mortality metric.

Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you again with another quiz. But first, this paper is from Kamal Khabbaz from Beth Israel Deaconess Medical Center and the Harvard Medical School, and it's going to assess whether left atrial appendage closure or exclusion during bypass surgery has impact on short-term outcomes.

So, Carolyn, here's your quiz. Do you think that patients receiving CABG with atrial fibrillation should undergo ligation of their left atrial appendage?

Dr Carolyn Lam: Well, I think there's definitely equipoise there. On the one hand, you're already in a surgery. Why not just ligate it? It's not like we need a left atrial appendage. And then on the other hand, I suppose it extends the surgery, it involves some risk, and we don't know if it actually prevents further events. Did I answer that right?

Dr Greg Hundley: Yes. Quite the politically correct answer, I think. Now, the objective of this study was to evaluate the impact of left atrial appendage exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. The study analyzed 250,287 CABG patients, of whom 7% received left atrial appendage closure. Only patients with a history of atrial fibrillation were included in the analysis, and the primary outcome was 30-day readmissions following discharge. Secondary outcomes included hospital mortality and stroke. And to assess the postoperative outcomes, the team utilized multivariable logistic regression models, and they adjusted for clinical and demographic co-variables.

Dr Carolyn Lam: Great. So what did they find, Greg?

Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial appendage exclusion was associated with a greater risk of postoperative respiratory failure, acute kidney injury, but it did not significantly change the rate of blood transfusions or the occurrence of cardiac tamponade. Second, left atrial appendage exclusion was associated with a nonsignificant reduction in stroke, no difference in in-hospital mortality, and a greater risk of 30-day readmissions. Number three, after adjusting for these co-variables, left atrial appendage ligation remained a significant predictor of this 30-day readmissions. And so, Carolyn, in this study, it looks like left atrial appendage exclusion during isolated CABG in patients with AFib is associated with a higher rate of 30-day readmissions.

Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else is in this issue. First is a pair of letters, one from Kai Wu regarding the article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared to Men With HFpEF: Insights From PARAGON-HF" and the response from Dr John McMurry. There are also two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and Inflammation: Mind the Gap" by Dr Lazzerini, and another entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms" by Dr Naveed Sattar.

There are two perspective pieces, "Establishment and Management of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by Dr Blake Thomson. There's an in-depth paper entitled "The Science Underlying COVID-19: Implications for the Cardiovascular System" by Dr Peter Liu. This is important. This one's an editor's pick, so don't forget to read this.

There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with ST Elevation: Looking Behind the Masquerade." In Cardiology News by Tracy Hampton, she reviews the literature and highlights three papers, one, "A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors" in Cell 2020; two, "Noninvasive Localization of Cardiac Arrhythmias Using Electromechanical Wave Imaging" in Science and Translational Medicine 2020; and three, "Somatic Gene Editing Ameliorates Skeletal and Cardiac Muscle Failure in Pig and Human Models of Duchenne Muscular Dystrophy", and that in Nature Medicine 2020.

For the President's Page, we have a piece by Keith Churchill, who's the Executive Vice President and CEO of Yale New Haven Hospital entitled "The Compelling Need to Address Uncertainty, Anxiety, and Financial Peril for Patients".

There's Highlights from Circulation Family of Journals by Sara O'Brien, including "Factors Associated With Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results From the ORBIT-AF" from Circulation Arrhythmia and Electrophysiology. There's "Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from Circulation Cardiovascular Imaging. There's also "The Impact of a 10 Rules Protocol on COVID-19 Hospital-Related Transmission: Insights from Padua University Hospital in Italy" from Circulation Cardiovascular Interventions. There's "The Association of an AMI Readmission-Reduction Program with Mortality and Readmission" from Circulation Cardiovascular Qualities and Outcomes. And finally, "Treatment Differences in Chronic Heart Failure Patients with Reduced Ejection Fraction According to Blood Pressure" in Check HF, and that's in Circulation Heart Failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few Research Letters that I reviewed. First is from Professor Puck Peltenburg, and the Research Letter involves children and adolescents from Brugada syndrome families in which only the SCN5A mutation carriers develop a type one ECG pattern induced by fever. And the second research letter is from Dr David Saadoun, and this evaluates the long-term outcome and prognosis factors associated with isolated aortitis. And then finally, Carolyn, there's a very nice piece related to the current status of cardiovascular medicine in Israel from Professor Ran Kornowski at the Rabin Medical Center.

Well, Carolyn, what a packed issue we have, and how about now we get on to that feature discussion?

Dr Carolyn Lam: Let's go, Greg.

Dr Greg Hundley: Well, listeners, we have a wonderful feature discussion for you in this next segment. We have Professor Keith Fox from Edinburgh and our own associate editor, Professor Stefan James from Uppsala. And we're going to discuss anticoagulation and antiplatelet therapy and rivaroxaban and aspirin and results from the COMPASS trial.

Keith, could you tell us what was the background information and what was the hypothesis that you wanted to test with your study?

Professor Keith Fox: The hypothesis was whether the combination of a very small dose, a quarter of the dose tested here, of a NOAC alongside an antiplatelet would be superior to aspirin alone, or we also tested a half dose of the NOAC by itself. And the overall trial showed that the quarter dose of rivaroxaban plus aspirin was substantially superior to aspirin alone in preventing cardiovascular death, MI, and stroke, with its biggest impact on strokes and cardiovascular death. So that's the trial as a whole.

But our specific goal here was to look at the question of net clinical benefit because clinicians are challenged by any therapy that has a balance of both potential hazard, like bleeding risk, and benefit. So what we analyzed here were the pre-specified characteristics of net clinical benefit in terms of life-threatening and major bleeding into a critical organ, plus cardiovascular death, MI, and stroke. And I asked the question, what was the net clinical benefit?

Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit about what population you were looking to understand net clinical benefit, and then what was the study design?

Professor Keith Fox: This is the whole of the COMPASS trial without the arm that tested rivaroxaban alone, because that did not show significant benefit. So this is the remaining 18,000 patients, double-blind randomized trial. And the trial, as a whole, was stopped early on the recommendation of the DSMB because it met the criteria for benefit by four standard deviations. Now, what's unusual about this is the population of our patients and vascular risk. So these are people who in the past would just be treated with aspirin. So they're not post-MI. They are people with chronic vascular disease, either peripheral or coronary. And in the past, on top of standard secondary prevention care, they would only have got aspirin.

Dr Greg Hundley: And what were the results?

Professor Keith Fox: There was a 20% reduction in terms of the net clinical benefit favoring the combination of rivaroxaban and aspirin, and that net clinical benefit being the combined impact of cardiovascular death, MI, stroke, fatal bleeding, or bleeding into a critical organ.

Dr Greg Hundley: And did you find the same results in, for example, older versus some of the younger patients? Or were there any other high-risk subgroups, those with impaired renal function or those with heart failure where you saw particular differences?

Professor Keith Fox: Yes, Greg. This is a really important issue. If one looked at the whole trial, the number needed to treat to prevent one of these adverse events, N equals 52. But then if we looked at some of the higher-risk cohorts, which we defined prospectively ... For example, these were the risk factors like polyvascular disease, impaired renal function, ambulant heart failure, or diabetes. And if you had all four risk factors, the number needed to treat was nine. If you had three risk factors, it was 12. Two risk factors, 31. So I think there's clearly a message for clinicians to be able to identify people with a combination of these risk factors, one or more, in order to get the most benefit and the least hazard.

Dr Greg Hundley: Very interesting. Any speculation on mechanism?

Professor Keith Fox: Yes. One of the things that we've done in the past is we've hammered one antithrombotic pathway. Like, for example, we've used more and more potent anti-platelets or combination of anti-platelets. But perhaps one of the things that we've forgotten is the fact that the platelet activation pathway is triggered by thrombin activation and vice versa. So the concept that was new behind the whole COMPASS study was that augmentation of the antithrombotic effects by combining a very small dose of a novel anticoagulant would be beneficial. And the critical question is, would it be sufficiently beneficial without producing a lot of bleeding? So that's why we did this particular analysis.

Dr Greg Hundley: So lower doses of some of these drugs. Well, Stefan, can you help us put these study results into context with what we know today about using aspirin alone, rivaroxaban, et cetera?

Professor Stefan James: The reason I think this study's so important and interesting is that, first, it's a very common population that we see now in the practice, patients with a stable phase of atherosclerotic disease, both coronary and peripheral vascular. And we need to take care of these patients better. Until now, we have not had very great alternatives for these patients. Now, we've learned what Keith said, that if you combine a low dose of both anti-platelet and antithrombin, you can inhibit and reduce the risk of ischemic events. And the other important finding here is that, I think conceptually very interesting, that if you are able to reduce their number of ischemic complications or thrombotic complications, but not doing that to such an extent that bleeding increases too much, not to an extent that bleeding causes fatal events, then you can find a nice balance between safety and efficacy that can lead to substantial reductions and improvements in terms of the clinical benefit.

And that's what we see here in this trial. You can see that there is a reduction of thrombotic events, ischemic events, and there is also some bleeding, but not to such an extent that it affects overall survival and the overall event rate in these patients. And particularly in patients at high risk that you pointed out, these patients have a very high event rate. Although the relative benefit is similar, the absolute benefit is quite impressive.

Dr Greg Hundley: Just very exciting to me. Very low doses of some of these common drugs. What's the next study in this field, Keith?

Professor Keith Fox: We've got a big gap because we know that modern dual antiplatelet therapy works really well after an acute coronary syndrome and it's highly effective. In the longer term, we know, for example, from some of the studies with ticagrelor that there are cohorts that do well for a period of time after ACS, but really we don't know the bridge between this period and the long term and what role this therapy may have after essential dual antiplatelet therapy.

Dr Greg Hundley: Stefan, do you have any thoughts?

Professor Stefan James: I agree with Keith. This transition period, when is patient transitioned from being an acute coronary syndrome patient to a chronic coronary syndrome patient? When does that happen? And then probably it differs between individuals and type of events, and so we need to understand more of when is this patient acutely affected and when do we need potent dual antiplatelet therapy? And when can we transition to a more stable phase in which we can inhibit thrombotic events, ischemic events, but not increased bleeding to such a degree that it affects overall survival? And so I think we need to learn a lot more about that transition period and these subgroups of patients of different risks and risks of ischemic events and bleeding events.

Dr Greg Hundley: Keith, how would you go about conducting a study in that regard?

Professor Keith Fox: I think really one of the very interesting questions is whether the combination of the standard of care of, for example, aspirin and ticagrelor may be better, worse, or the same than this therapy instituted at the end of the period of essential dual antiplatelet therapy. And we need to know that.

Dr Greg Hundley: In closing and summing up, Keith, are there any concepts that we want to take home here?

Professor Keith Fox: I think that there are two key concepts. One is the synergy between the anticoagulation system and the antiplatelet system, with the potential to use very low doses, to minimize bleeding risk, yet have the benefits. That is the first concept. The second concept is that these chronic vascular disease patients Stefan has described are at continuing risk of vascular events, especially stroke, myocardial infarction, and cardiovascular death. And these can be modified.

Dr Greg Hundley: And Stefan, any thoughts from you in closing?

Professor Stefan James: I think this paper and the work that Keith has described is fantastic and fascinating to think about because these populations are incredibly large, and they are not doing well. They have a high risk of events, and we tend to forget that, and so we need to both identify them and start treating them now, as we have some evidence, but we'll also need to learn more of how to identify them, how to select them appropriately, and how to identify the transition from acute events to chronic events or current chronic phase of the disease.

Dr Greg Hundley: Well, listeners, I want to thank both Professor Keith Fox and our own associate editor, Professor Stefan James, for this very interesting presentation of lower doses of anticoagulant and antiplatelet therapy in patients with chronic vascular disease and really being able to reduce events and diminish bleeding.

On behalf of Carolyn and myself, we want to wish you a great week and look forward to catching you next week. Take care.

This program is copyright of the American Heart Association 2020.