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Circulation on the Run

Jun 8, 2020

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 associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue?

Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers.

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

Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified.

Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message?

Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations.

Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer.

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

Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity.

Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg?

Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy.

Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date.

Dr Greg Hundley: So Carolyn, what did they find here?

Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy.

Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic.

And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction.

Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now.

Dr Greg Hundley: Look forward to it.

Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important.

Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day.

And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone.

Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that?

Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other.

So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well.

Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results?

Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication.

So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a really effective way of reducing important future vascular risk, whether that's cardiovascular risk consisting of MI related end points, stroke, peripheral ischemic end points, including amputation, which was significantly reduced in the trial, and within the subgroup of those with diabetes.

So it's a matter of balancing those, but I do think with careful decision-making on the part of the physician, with discussion with the patient, with their understanding of the risks and benefits of intensifying the antithrombotic regimen beyond aspirin, there are a substantial number of patients who could benefit.

Dr Gregory Lip: I whole fully agree with Deepak's comments. And we do have to bear in mind also that risk is also a fairly dynamic process and we may well be assessing the patient as the one off initially while we are initiating treatment. But of course risk, whether from cardiovascular risk or whether from bleeding risk particularly, also is influenced by increasing age and by incident comorbidities, which really means that risk reassessment should be performed in every patient we contact. With bleeding risks in particular, there are modifiable bleeding risk factors that we can mitigate. So proactive assessment or rather reassessment of risks, whether both from cardiovascular events and/or bleeding, is necessary as we follow up these patients.

Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build a bit on your analogy of no free lunch. And maybe sort of a general question do you both, because it seems like we've got a bonanza of a buffet now when it comes to diabetes, especially with the new anti-diabetic drugs. So how do you think this fits in altogether? You talked about Statins. We now talk about low dose rivaroxaban in addition to aspirin, and you think diabetic patients should be treated with all? Maybe Deepak first, then Greg.

Dr Deepak Bhatt: What a terrific question. In fact, that was asked of me by the late-breaking clinical-trial panel clinical trial panel. They said, "Well, how does it fit in? Because these data look terrific, but there's also other new diabetes drugs and approaches." So for sure, I would say again, barring a real contraindication, I would say everyone that we're talking about here should be on a statin and preferably if they can tolerate it, a high intensity statin.

And if that doesn't do the trick in terms of LDL goal, I would say zetomyde. And potentially if they're in a region of the world where it's affordable a PCSK9 inhibitor. Then beyond that, I think we've got to pay attention to triglycerides these days, not just LDL cholesterol and if it's some patient that's sort of like REDUCE IT, well then, they should be on eicosapentaenoic. So we can modify LDL related and triglyceride related risks without too much effort or too much in the way of side effects. Then beyond that, I would say, we've got to think about blood pressure, inadequate control, especially in those with diabetes, but even those without that have cardiovascular disease. And then we have to think about glycemic control. And I don't mean the old-fashioned way, but I mean with some of the newer drugs. SGLT2 inhibitors in particular have been found to be useful for both.

That's just the glycemia control part of things, more importantly, cardiovascular outcomes. In particular, heart failure and renal related outcomes. And then GLP 1 agonist as well have been shown to be very useful once more modifying cardiovascular outcomes, including atherosclerotic outcomes. So there is, as you say, quite the buffet. And assuming a patient can tolerate that polypharmacy and afford it, I do think the majority of patients with diabetes should be treated that well. And that's of course on top of lifestyle modification, weight loss is particularly important, plant-based diet, et cetera.

But on top of that, then, with all those things that are being done and a patient is still at high ischemic risk but is at low bleeding risk, that's where I think, even in the deceptively stable appearing outpatient, it's worthwhile just running a mental checklist and saying, "Okay, are they on an SGLT2 inhibitor? Check. Did In someone measured their triglycerides? Check." And then on that checklist is, "Yeah, could they tolerate being on more than just aspirin alone in terms of bleeding risk? And if the answer to that is yes, might they benefit from adding this on?" And there are a lot of patients these results apply to, and I think a proportion of those patients who are otherwise optimally treated for their risk factors are the ones to target.

Dr Carolyn Lam: Beautifully put. And Greg?

Dr Gregory Lip: Deepak does raise an increasingly applied concept in how we approach our patients at high risk of cardiovascular events. That's the so called integrated or holistic approach to management. Because we have in the past tended to just focus on one strand of management. For example, we may well just be putting a lot of focus when on the analytic reduction and ignoring the rest. Well, we can't do that these days. We have to manage the whole patient and not just the bit of the patient. And this brings in this holistic approach, this integrated approach. And I think Deepak summarized that very nicely. It may require a number of medical approaches or medication-based approaches, but we have to practically look at the comorbidities like blood pressure reduction and also the lifestyle changes that Deepak's already summarized. So a holistic and integrated approach to our care of these patients. And in fact, some of the more recent studies showed nicely how this results in better outcomes in our patients at high cardiovascular risk.

Dr Carolyn Lam: And in fact, those were exactly the last words of your editorial. A holistic and integrated care approach. Beautifully done, thank you both so much for this excellent discussion. Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again. Next week.

Dr Greg Hundley: This program is copyright the American Heart Association 2020.