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Circulation on the Run

Jun 17, 2019

Dr Gregory Hundley:       Welcome everyone to the June 18th edition of Circulation on the Run. I am Dr Greg Hundley, Professor of Internal Medicine and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

                                                In today's issue we're deviating from our common format due to some scheduling difficulties. So, rather than our traditional coffee chat in this program I'm going to have a large gulp of coffee and present results from several exciting papers. Then we'll turn over the second half of our program to Dr Carolyn Lam for our feature discussion.

                                                Now, I promise this is a one-time deviation and we will return to our common chat format in early July. But, before I launch into my presentations I did want to introduce what will transpire with Carolyn. She will be discussing an exciting paper from the Adelaide Medical School at the University of Adelaide in Australia.

                                                Some have wondered whether the persistence of a patent arterial venous fistula post-kidney transplant may contribute to ongoing maladaptive cardiovascular remodeling. To address this issue Carolyn will be discussing with authors whether ligation of this AV fistula may reverse this maladaptive remodeling. And like you, I'm excited to listen to that discussion. But before that let me review several of the other distinctive papers on this issue.

                                                The first one is entitled “Individual Treatment Effect Estimation of Two Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.” They are the results from the RE-LY trial. The corresponding author is Professor Frank Visseren from the University Medical Center of Utrecht in Utrecht University.

                                                The study emanates from the randomized evaluation of long-term anticoagulation therapy or the RE-LY trial. In which high dose dabigatran, that's 150 milligrams twice daily, was found more effective in prevention of ischemic stroke and systemic embolism than low dose dabigatran which is 110 milligrams twice daily.

                                                But this occurred at that expense of an increased risk of gastrointestinal bleeds. Importantly however, the absolute treatment effect of dabigatran in both doses, likely differs between individuals. And therefore, individual treatment effect estimation has the potential to identify patients who have a favorable trade off and absolute benefit and harm from dabigatran compared with no treatment, and to select the optimal dose for each individual patient.

                                                So in this study, the investigative team derived and validated a prediction model for ischemic stroke and systemic embolism and major bleeding in patients with atrial fibrillation from three treatment arms of the RE-LY study. They had 11,955 individuals in the derivation cohort and 6,158 in the validation cohort. And they evaluated the patient characteristics of sex, age, smoking, anti-platelet drugs, prior vascular disease, diabetes, blood pressure, estimated glomerular filtration rate, and hemoglobin.

Dr Gregory Hundley:       Well, what were the results? Well the five-year absolute risk reduction, for ischemic stroke and systemic embolus minus the five-year absolute risk increase for major bleeding, when comparing the high to the low dose of dabigatran yielded a net benefit in 46% of patients. And therefore, the authors conclude that the absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics.

                                                And perhaps down the road such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine its optimal dose of administration. Well, how 'bout that? And let's go on to the second paper entitled “Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness and Safety, or EMPRISE Study.

                                                And the corresponding author for this study is Elisabetta Patorno from Brigham and Women's Hospital in the Harvard Medical School. So, as a background in a different study to this, the EMPA-REG OUTCOME trial showed that Empagliflozin an SGLT2 inhibitor was found to reduce the risk of hospitalization for heart failure by 35% on top of standard of care in patients with Type 2 diabetes and established cardiovascular disease.

                                                Well, the current study, The Empagliflozin Comparative Effective and Safety or EMPRISE Study was designed to assess empagliflozin's effectiveness, safety, and health care utilization in routine care from the period of time between August of 2014 through September of 2019. And the author's report on the first interim analysis in which they investigated the risk of hospitalization for heart failure among Type 2 diabetic patients initiating empagliflozin vs. sitagliptin.

                                                The investigators used two commercial and one federal Medicare claims data source from the U.S. and identified a one-to-one propensity score matched cohort of 16,443 pairs of Type 2 diabetes patients that were greater than 18 years of age initiating empagliflozin or sitagliptin. The average age of the participants was approximately 59 years.

                                                And almost 54% of the participants were males and approximately 25% had records of existing cardiovascular disease. So compared to sitagliptin the initiation of empagliflozin decreased the hospitalization for heart failure risk by 50% over a mean follow-up of 5.3 months. And the results were consistent in patients with and without baseline cardiovascular disease for both the empagliflozin 10 milligram or 25 milligram daily dose. Or analysis comparing empagliflozin vs. dipeptidyl peptidase-4 inhibitor class all comers.

                                                Thus, in conclusion, in this first interim analysis from EMPRISE, the investigative team showed that compared with sitagliptin the initiation of empagliflozin was associated with a decreased risk of hospitalization for heart failure among patients with Type 2 diabetes as treated in routine care with and without a history of cardiovascular disease.

Dr Gregory Hundley:       Well, now we're going to turn our attention to red meat. And this next study was entitled, The Consumption of Meat, Fish, Dairy Products, Eggs, and Risk of Ischemic Heart Disease. It's a Perspective study of 7,198 incident cases among 409,885 participants in the Pan European Epic Cohort. And the corresponding author is Professor Timothy Key from The University of Oxford.

                                                Some of the background here, met analysis of previous prospective studies have suggested that intake of processed meat maybe associated with a higher risk of ischemia heart disease whereas, unprocessed red meat might not. For dairy products and eggs, systematic reviews of prospective studies have reported no consistent evidence that higher intakes are associated with a higher risk of ischemic heart disease.

                                                Other studies have shown that fatty fish consumption may reduce the risk of ischemic heart disease, it is a rich source of long chain N3 fatty acids. And meta-analysis has suggested even an inverse association between overall fish consumption and mortality from ischemic heart disease.

                                                So, hear in this cohort: we're going to evaluate all of these. Accordingly Key, and his co-authors report the relationships of these foods with risk of ischemic heart disease in the European prospective investigation into cancer and nutrition, the EPIC study, and that again is a cohort of a half million men and women from nine European countries followed for 12 years to examine the association between the intake of animal foods and the occurrence of ischemic heart disease.

                                                The author's found that higher consumption of red, unprocessed and processed meat was positively associated with the risk of ischemic heart disease. None of the other animal foods examined were positively associated with this risk. And intakes of fatty fish, yogurt, cheese and eggs were modestly, inversely associated with the risk.

                                                In addition, the red and processed meat were associated with plasma non-HDL cholesterol and systolic blood pressure. And this finding is of interest as possibly these other variables could serve as mediator of the association between red or processed meat and future ischemic heart disease. It is important to note that while these results are of interest to those concerned with the future adverse cardiovascular effects related to the consumption of red meat, one cannot infer causality and other studies would need to be designed to address causal relationships.

                                                The last paper that I'm going to present during the coffee gulp, emanates from the basic science arena. And it is entitled The “Shear-Induced CCN1 Promotion of Atheroprone Endothelial Phenotypes and Arthrosclerosis. And the corresponding author is Dr Fan-E Mo from the National Cheng Kung University College of Medicine.

Dr Gregory Hundley:       The matricellular protein CCN1 has been implicated in arthrosclerosis based on its expression in arterial segments with evidence of arthrosclerosis. And this study evaluated the relationship between sheer stress, both laminar and oscillatory at the site of atherosclerotic liaisons and molecular markers of pathophysiologic process involved in the progression of arthrosclerosis.

                                                The authors found that sheer induced CCN1 and its receptor integrin, alpha six, beta one, instigate atheroprone phenotypic changes in endothelial cells via activating NF kappa beta. Because the activation of NF kappa beta further up regulates the expression of CCN1, alpha six, and beta one, atheroprone flow creates a positive feedback to sustain atherogenesis.

                                                In addition, disrupting CCN1, alpha 6 beta one engagement by a specific CCN1 mutation, or by a peptide antagonist unhindered atherogenesis in mice. So what are the clinical implications of these findings? That's something Carolyn would ask me. Well, it appears that CCN1 alpha 6 beta one engagement represents a novel therapeutic target for arthrosclerosis.

                                                These data demonstrate a causative role of CCN1 in atherosclerosis via modulating endothelial phenotypes. And CCN1 binds to its receptor integrin alpha 6 beta one to activate NF kappa beta, thereby instigating a vicious cycle to persistently promote atherogenesis. Perhaps in the future T1 me medics may further be optimized to treat arthrosclerosis.

                                                Well everyone, that concludes the first portion of this June 18 edition of Circulation on the Run and now it's time to move on to Carolyn's discussion of our featured paper.

Dr Carolyn Lam:                Cardiovascular disease remains the major cause of death in kidney transplant recipients. And today's featured paper has important implications for the management of this cardiovascular risk following kidney transplantation. I'm so excited to be discussing it, and I'm going to let the corresponding author Dr Toby Coates from Royal Adelaide Hospital tell us all about it, and so happy to also welcome our editorialist Dr Patrick Mark from University of Glasgow.

                                                Toby, could you please tell us what inspired you to do this remarkable study?

Dr Toby Coates:                We're very interested in obviously our patients surviving as long as they possible can after kidney transplantation. And we noticed that many of them having had a successful kidney transplant, still had functioning AV fistulas. Now of course the AV fistula, is a connection between the artery and the vein that enabled us to access the circulation after hemodialysis. Which around the world is probably the most, is the most common form of dialysis practice performed.

                                                So many of these patients sustained 20 years down the track after successful transplants still had these very large functioning left to right shunts, on the basis of their dialysis history. So we had a couple of patients who developed quite severe cardiac failure and we noticed that when we ligated the AV fistula, their back got dramatically better.

                                                So, as a consequence of that, we went to look at the ligature and we couldn't find any randomized control trial that told us what the best thing was to do, post-transplant with these fistulas. So we decided that what we would do be use the state of the art cardiac magnetic resonance imaging, or cardiac MRI to assist the cardiac function with myocardium thickness in our patients and then randomize a group of stable transplant patients to ligation or not.

                                                And then follow that up with cardiac MRI six months down the track to see what happened. And so that was the basis of the study that we performed. The first randomized controlled trial of the effect of ligation of the AV fistula on the left ventricular mass, that was the prominent one for trial.

Dr Carolyn Lam:                You know, Toby, just to let you know right there, I thought it was so incredibly novel. So I'm a heart failure specialist and we know that shunts are associated with high output cardiac failure, and yet, I personally had never questioned this, so I thought this is incredibly novel and it's important. But please, tell us all about the results.

Dr Toby Coates:                We were delighted to say that there was a very significant reduction in the left ventricle mass. In fact, the main decrease was 22.1 grams compared to the control arm in whom the cardiac mass actually went up 1.2 grams. So, then we mobilized the body surface area, the reduction of the left ventricular mass index dropped by 11.8 grams per metered square.

                                                Now, this is quite remarkable for me doing the study because I've never seen an intervention, I've never seen an intervention where every single patient improved with the ligation, every single patient there was an improvement in the cardiac parameters. Never seen anything like it in the pre and post of the ventricular mass it really came down. So that was quite remarkable.

                                                And the second thing that really impressed me at the time, was the improvement in the BMP's, and we measured the brain maturated peptide, and being a methodologist that's clearly something that's of interest to us and we saw a substantial reduction. It's statistically significant reduction in BMP as well.

                                                The patient themselves, some of them recorded quite significant improvement in exercise tolerance afterwards. And we had, as I mentioned before in a couple of patients, not in the study but outside of the study, subsequently when they're presented with profound right heart failure, the ligation of the AV fistula made a huge difference to them symptomatically.

                                                So that was sort of confirming all of the things that we thought along the way. Pleasingly we didn't see any change in kidney function. So, we were concerned that there might have been on the basis of some non-controlled studies in the past, that there might have been a deterioration in the estimated glomerular filtration rate, or eGFR. We didn't see that.

                                                And we didn't see any significant change in the blood pressure either. Which is some of us have previously reported. Closing the fistula itself, is a very trivial procedure. It's usually done as an outpatient, so a day procedure. So it's not resulting in coming to the hospital. And the only complications, really were lots of local redness and some pain, potentially from the fistula where in the ligated.

                                                So, we thought this was remarkable. An outpatient procedure that could significantly reduce the left ventricular mass by 22.1 grams over the six month period that was associated with minimal side effects and complications. And when you think about that, that's sort of equivalent really to taking an anti-hypertensive medication for six months. That magnitude of reduction with ventricular mass which clearly from the patient's point of view is much preferable to adding more medication to an already over-burdened tablet loading in your patients with kidney transplants. So we were very pleased with that result altogether.

Dr Carolyn Lam:                Thank you Toby, and we in turn were very pleased to be publishing this in Circulation. Likewise, Patty, if I may, I love your editorial. First, let me tell everybody who's listening out there. Go pick up the editorial and look at the figure. It is so cool. It shows pros and cons of arterial venous fistula ligation in these patients. But could you please share some thoughts Patty? I mean you covered the perspective just so well.

Patrick Marks:                   I must give the credit to my co-author who actually drew the figure himself. So Chris Eaves rather myself. We were really impressed with the study and we're really delighted to write an editorial for it. It's just one of those studies that I have to say, you know, you kick yourself and you wish you'd done it. With all the world of observational data showing that creation of a fistula appears to be associated with an increase in LV mass obstruction by echo and angio and bicartic MR in smalls studies.

                                                But it's taken a long stat to move from that to actually doing a randomized control of ligating the fistula in people with you know, stable functioning transplants. We were really, really impressed with Toby and his team for undertaking this study. And until we'd gone through the results, they're really very impressive.

                                                The magnitude of reduction LV mass is very impressive and also the changing BMP was really nice to see. One of my comments of the study were, was interesting because as methodologists we are aware of the idea arteriovenous fistula as being the axis for dialysis. And we sometimes feel uncomfortable by ligating this because we know if the transplant was to fail, how much patients need a functioning fistula. And that's the one thing I'm still curious, like and I still offered some comments in the editorial were, that while there's doubt that the cardiovascular benefits demonstrated by Toby's study are really very impressive.

                                                I wondered about the implications out with the study came down the line, you know would there be some of these patients whose kidney transplant function would decline? And there may be regret of losing the access. We mentioned there is some inconvenience, it is an operative procedure to loosen the fistula. So there are some things to think about in the study, but overall, I can't help saying just how impressed I am that they managed to do this trial in a proper randomized, controlled trial form. It's really, really impressive in using the cardiac MR endpoint is it seems quite a secure way of assessing this.

Dr Carolyn Lam:                Those are great points, Patty. Toby, any response to that.

Dr Toby Coates:                Look it's really very interesting as a transplant pathologist for the last 20 years, one of the biggest, I guess it's a bit of a misconception. When a fistula has been present for 10 or 15 years and still there to come back and try and reuse it for dialysis access after that period of time, in my experience anyway, also very difficult to reuse those fistulas and the surgeons end up having to create a new one anyway.

                                                They frequently become quite aneurismal, they get very large and unsightly and the volume of the shunt is significant and often we find that as an access they don't work as well. So I personally don't have a huge concern about closing them. Now I agree with you, these patients were stable, longstanding and we assessed that the risk is, we need to go back onto hemodialysis was small.

                                                But you are absolutely right, I mean, it is possible that something could have come out of the blue and maybe a patient would be disappointed that that access that they'd had for so many years was no longer available. So that is, the caveat on the study, but thankfully so far out, some of these patients five or six years down the track, we haven't had anybody need to go back on dialysis, so it's been good.

Dr Carolyn Lam:                Yeah, it really says to me as well, that patient selection is important exactly like you emphasized, and you, in the editorial Patty. But from a cardiology standpoint, too, are there plans to perhaps do studies with hard, clinical endpoints? What do you think are the next steps? Maybe I'll let Toby go first, then Patty.

Dr Toby Coates:                We think now with this study done, the next thing is to have a larger study with significant cardiovascular endpoints. Which I obviously would be cardiac failure and acute coronary events. So the two things that would seem in my mind, and I think that needs to be multi-centered, preferable international if we can.

                                                And one of the really positive things about the highlight from the American Heart Association is that we've had people reach out to us from France and all around the globe saying that they'd be interested in participating, you know in a multi-centered trial. So, I think that's what we need to do, and clearly you don't it’ll have to be a constant endpoint, or not. I'd be interested in Patty's thoughts about that, right if you had some guidelines and some suggestions.

                                                And then obviously would be randomized, controlled trial looking at those hard endpoints with probably some sidearms doing cardiac MRI as well, and potentially more heart functioning tests. So yes, I think this is just the beginning, we do need a hard endpoint trial to really nail this completely.

Patrick Marks:                   Yeah, I'll just come in there and just come on to that Toby. I completely concur with what you said. I think there's been quite a provocative editorial a few years back, and suggesting that while there's lots of studies in chronic kidney disease, end stage renal disease, kidney transplant patients avoid LV mass, really it hasn't yet been translated into actually leading studies in the integration of LV mass and end stage renal failure haven't really yet translated into mortality benefits.

                                                And I think we need to move to a bigger study. It's really beautiful that you've been able to demonstrate LV mass falls naturally with ligation. And it's impressive that it just happens so consistently across your population in the intervention arm. But we need to move on to a longer trial with hard clinical endpoints. Certainly heart failure, certainly cardiovascular mortality, [be]cause there's plenty of reasons to believe that producing LV mass in these patients might have benefit both for heart failure, whether that's heart failure, heart injection fraction, or whatever, I'll leave that to Carolyn's judgment to help us with that.

                                                But also, if we can reduce LV mass and then we may be able to reduce arrhythmia burden which again is when these things we worry about in end stage renal disease, again, your answer for that is, that in addition to the heart endpoints you should be able to also add in some patient afforded outcomes in a larger study. Or something like an exercise tolerance quota of quality of life.

                                                All this has started has journey from the surrogate endpoint of left ventricular mass into a bigger outcome study and I can't wait to see how you get on with it.

Dr Carolyn Lam:                I can't wait either. And I'm sure the audience is sharing all our enthusiasm as well. Thank you so much Toby and Patty. I really learned so much. You heard it right here on Circulation on the Run. Thank you for joining us this week. Don't forget to turn in again next week.

                                                This program is copyright American Heart Association 2019.