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Circulation on the Run

Oct 28, 2019

Dr Carolyn Lam:  Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results.

Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers.

Dr Carolyn Lam:  So... What did they find?

Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients.

Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized.

Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP.

Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes.

Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study?

Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more.

Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells.

Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find?

Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart.

Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy.

Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them?

Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer.

Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap.

Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece.

Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter.

Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock.

Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy.

Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study?

Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer.

Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population?

Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk.

Dr Greg Hundley: And who did you include in this study?

Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention.

Dr Greg Hundley: And how many subjects were in your study? Was this a large study?

Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations.

Dr Greg Hundley: So what did you find? What were your results?

Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis.

To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis.

Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis.

Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women?

Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding.

Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies?

Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer.

And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear.

Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation?

Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial.

Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years?

Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier?

Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy.

And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week.

Dr Carolyn Lam:  This program is copyright American Heart Association 2019.