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Circulation on the Run

Apr 27, 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, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today looks at the use of Apixaban versus Warfarin, so a trial between the two in patients with atrial fibrillation and advanced kidney disease. But before we get to that, how about if we break away, grab a cup of coffee and go through some of the other important papers in this issue?

Dr Carolyn Lam: Yeah, and why not start with talking about our gut and fiber in the diet. Now, we know that a diet poor in fiber is associated with the prevalence of hypertension, but what are the underlying mechanisms? Well, this first paper I want to talk about is from Dr Marques from Baker Heart and Diabetes Institute in Australia and colleagues who basically performed a nice series of mouse experiments and found that a diet lacking prebiotic fiber led to a gut microbiome that was pro hypertenenogenic facilitated the development of cardiac hypertrophy in germ free mice.

Even in the absence of fiber, gut metabolites called short chain fatty acids usually produce from the fermentation of prebiotic fiber by the gut microbiota, but they were able to protect against the development of hypertension, cardiac hypertrophy and fibrosis in a preclinical model. This cardioprotection involved short chain fatty acid receptors, and a decrease in the ratio of sodium to potassium excretion and changes in genome white methylation that supported higher levels of T regulatory cells.

Dr Greg Hundley: Oh my goodness, Carolyn. So I need to know what I eat for lunch? What's the take home message here?

Dr Carolyn Lam: Lots of fiber and definitely not the low fiber westernized diet, which may underlie hypertension. And how? Through deficient short chain fatty acid production and thus the take home is maintaining a healthy, short chain fatty acid producing microbiome is important for the cardiovascular health.

Dr Greg Hundley: Wow, Carolyn. I love that article because it really helps provide some perspective on all the diet information that we've been receiving lately. Well, my paper is from doctor ... another Carolyn, but this is Carolyn Ho from Brigham and Women's Hospital-

Dr Carolyn Lam: I love her.

Dr Greg Hundley: ... And it involves hypertrophic cardiomyopathy and left ventricular systolic dysfunction. So Carolyn, the term end-stage has been used to describe hypertrophic cardiomyopathy with left ventricular systolic dysfunction. And that's defined when someone has hypertrophic cardiomyopathy and the LVEF is less than 50%. The prognosis of patients with this condition has been reportedly poor, but it's very rare in occurrence and therefore, the natural history really remains incompletely characterized. So what did the authors do in this study? They evaluated more than 500 patients from 11 high volume hypertrophic cardiomyopathy specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry or SHaRe registry. And they were used to describe the natural history of patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction.

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

Dr Greg Hundley: Number one, first overall, this group of patients, hypertrophic cardiomyopathy with left ventricular systolic dysfunction occurs in about 8% of those with hypertrophic cardiomyopathy. Although the natural history of left ventricular systolic function and hypertrophic cardiomyopathy is variable, 75% of those that have this condition experience adverse events including 35% experiencing a death equivalent at a medium of 8.4 years after developing their systolic dysfunction. In addition to clinical features, the genetic substrate appears to play a role in both prognosis, so there are multiple sarcomeric variants, and in the risk for incident development of left ventricular systolic function with hypertrophic cardiomyopathy due to variance in the thin filaments within those myocytes.

Dr Carolyn Lam: Nice. Thanks for that Greg. My next paper is a really interesting secondary analysis if you may, of the EXSCEL study. As a reminder, the Exenatide Study of Cardiovascular Event Lowering or EXSCEL assessed the impact of once weekly exenatide versus placebo in patients with type two diabetes and showed non-inferiority but not superiority for the primary MACE outcome.

Now, during this trial, while aiming for glycemic echo-poise, a greater drop-in of open label glucose lowering medications occurred in the placebo group, thus prompting the current authors, which is Dr Rury Holman from University of Oxford and their colleagues to really explore the possible impact of unbalanced open labeled drop-in of glucose lowering medication on EXSCEL outcomes. To our modern diabetes trial, they used three methodologies. One, drop-in visit, right censoring. Two, inverse probability for treatment waiting. And three, applying drug class risk reductions. Now, Greg, I could either quiz you on these methods or summarize the results, which would you prefer?

Dr Greg Hundley: Well, Carolyn, this calls for the infamous phone a friend. So one of the nice things we have at Circulation is a wonderful group of statisticians that really help us go through all the papers. But I sure would like to pick up the phone and call one of those folks now. But I think what I'm going to do ... maybe just give me the results of this study. That's what I prefer.

Dr Carolyn Lam: I thought you might say that. So the EXSCEL observed has its ratios for MACE remained robust after right censoring or application of the literature derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by the inverse probability treatment waiting approach. So I think the take home is that effects of open label drop in cardioprotective medications do need to be considered carefully when designing, conducting and analyzing cardiovascular outcome trials of glucose lowering agents. Do we have the perfect solution? Perhaps not, but this was a really important paper to just look at and study. So Greg, I can see that you are stats out, so I'm going to tell you a little bit more about other papers in this week's issue.

There's a research letter by Dr Zhang on transcription factor Kruppel-like factor 15 and how it regulates the circadian susceptibility to ischemia-reperfusion injury in the heart.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple of other papers. There's a nice in-depth piece from Dr Gregory Marcus from the University of California, San Francisco on how we evaluate and manage patients that have premature ventricular contractions. Dr Mori Krantz from Denver Health and Hospital Authority gives us an EKG challenge in someone that's had a needle stick. And then finally, there's a nice perspective piece from Dr Paul Armstrong from the Canadian VIGOUR Centre, department of medicine cardiology at the University of Alberta. And he really goes over nicely how we're going to do global collaboration to enhance cardiovascular care. What a great issue. And now onto that feature where we're going to hear a little bit about Apixaban and Warfarin in those individuals with atrial fibrillation and chronic kidney disease.

Dr Carolyn Lam: Let's go, Greg.

Today's feature paper really represents the first randomized data on NOAC versus warfarin in a very important group of patients, that is those with atrial fibrillation and advanced chronic kidney disease. So happy to have with us the corresponding author, Dr John Stanifer from Munson Healthcare, Traverse, Michigan. As well as our associate editor, Dr Chang-Sheng Ma from Beijing Anzhen Hospital in China. Welcome, welcome. So John, could you tell us the inspiration if you may, or the rationale, for doing this study?

Dr John Stanifer: This is a population that's near and dear to my heart as a practicing nephrologist. We care for so many patients with atrial fibrillation, particularly those on dialysis or those with advanced kidney disease. And as other practitioners and people taking care of this population will tell you, this is just such a confusing and challenging clinical problem to try to deal with. And then really this stems from that important clinical need that we recognize almost on a daily basis.

Dr Carolyn Lam: I just love that you shared that John, because coming from a nephrologist, and we're usually talking to cardiologists where we think about this all the time and have no idea what to do. So tell us about your study and what you found.

Dr John Stanifer: As you know, these were data that were taken from the Aristotle trial that was finished in 2011, that was really a landmark study that established the real superiority of Apixaban compared with Warfarin and the general population.

And it happened that within the study, there were several patients, 269 that had a creatinine clearance of between 25 and 30 milliliters per minute. We then took those data from those patients and compared really in this study, the safety of Apixaban compared with Warfarin within that subpopulation, and then compared that as an interaction with the safety of Apixaban versus Warfarin in patients with creatinine clearance of greater than 30.

Dr Carolyn Lam: And what did you find?

Dr John Stanifer: Well, in conclusion, we really found that among these patients with a creatine clearance of 25 to 30 MLs per minute in atrial fibrillation that Apixaban did cause less bleeding than Warfarin. And it appeared to be an even greater relative risk reduction when you compare that with the safety of Apixaban versus Warfarin and those with a less severe kidney disease.

Dr Carolyn Lam: It's truly the first time I've seen data like this. So congratulations John and thank you so much for publishing this paper with us at Circulation. Chang-Sheng, Circulation seems to be publishing a lot in the space of combined renal and cardiac disease, which is very interesting. Why was this paper so important to us as well?

Dr Changsheng Ma: It's a very important question for a clinical practice. The anticoagulation therapy in patient with advanced CKD. And observation or analysis have demonstrated inconsistent of findings regarding the net clinical benefit of warfarin in reducing the risk for stroke in patients with advanced CKD. The problem of Warfarin treatments in this patient group is dramatically higher bleeding risk. The current study also show that the bleeding risk was three- to four-fold higher in patient with advanced CKD compared to that in patient with creatinine clearance more than 30 milliliters per minute when treated with a Warfarin.

So these studies are our first randomized data for NOAC compared with warfarin in patients with advanced CKD. The results provide important information as to the safety of Apixaban in this special patient group with high risk of bleeding. With reduced risk of bleeding, we may expect net clinical benefits of Apixaban in preventing stroke in patients with advanced CKD.

Dr Carolyn Lam: Indeed. John, did you demonstrate that net clinical benefit or could you perhaps explain if future steps are needed to look at that a bit better?

Dr John Stanifer: Well, I think absolutely future studies are needed. You have to keep in mind that these were pre-specified groups within Aristotle. These are still post-trial data from this study and that absolutely we need studies that are powered to really compare the safety. I would add not just apixaban with warfarin, but I would also add placebo to that.

Dr Carolyn Lam: Interesting. Changsheng, you had some questions for John as well.

Dr Changsheng Ma: Yes. John, I had questions for you. If you take a randomized trial for the answer for this question, how many cases do you think?

Dr Carolyn Lam: How many cases of?

Dr Changsheng Ma: How many cases should there be for a sample size for a trial?

Dr John Stanifer: Well, you're really putting me on the spot here. I'll have to go back to my statistical days. Well, I think the easy part in the design of a trial for a question like this is that the event rates are so high. Whether that be for both safety outcomes related to hemorrhage and bleeding risks or primary benefit outcomes. So that would be very beneficial with that respect. But I think the key to designing a study ... and I know that there are several ongoing RENAL-AF and several others that are trying to examine this very question, but I think as a nephrologist, what we would kind of push back on a little bit is that there's no placebo arm to these trials. And I actually think that that would be a step forward even though that would be a very challenging thing, I think at this point to push for ... I think the nephrologist has kind of continued to push for that a little bit.

Dr Carolyn Lam: So John, that was beautifully answered. If I could ask you then, have these results influenced your practice even now?

Dr John Stanifer: Well, prior to this, we've been a little bit nervous with Apixaban, even though observational data may suggest that it would be safer or potentially usable in patients with advanced kidney disease. But part of the real conundrum and some of the challenges that come up are really around dosing of Apixaban. And they say, "Well, gosh, if they're in stage renal disease, yeah, maybe it's too bad. Maybe the kidney function is way too low and we need to kind of reduce it based just on that one criterion as opposed to the three criteria laid out in Aristotle." So I think that was some of the challenges. but I think after seeing these data and seeing the safety relative to Warfarin was really there in this patient group, yeah, it has influenced me a little bit. I am a little more adamant about switching patients.

Dr Carolyn Lam: Yep. Chang-Sheng, do you agree with that? What do you think are next steps here?

Dr Changsheng Ma: Because clinical practice is different, apparently, more evidence is badly needed to guide the future clinical practice because the patients with creatinine clearance even less than 25 milliliters per minute. And those in dialysis were not included in any of the pivotal studies of NOAC.

Dr John Stanifer: Absolutely.

Dr Changsheng Ma: It is still uncertain whether this patient will benefit from Apixaban or other NOACs. So in this study, even the significant less measured bleeding events were observed. I think the all-cause mortality was not different between the two groups. So the next step we should design a new trial to confirm whether Apixaban will really improve the prognosis of the patient with advanced CKD and AF.

Dr John Stanifer: I will second that. For sure we want to answer that very important efficacy question related to this class of medications.

Dr Carolyn Lam: Efficacy and patients on hemodialysis. Wow. This really just opens up a lot, but you're right. It's such tantalizing information that you see in ... so thank you so much John, for publishing this paper with us. Chang-Sheng, it's such a great paper. I remember the discussions we had during our editors’ discussions and it's so nice to see it out in print. I'm telling you, audience, you have to get hold of this paper. It will change this field I think and will lead to further trials exactly like you've heard here, and that we've put John on the spot to describe.

Dr Carolyn Lam: Thank you very much gentlemen for a wonderful discussion. Thank you, audience, for joining us. You've been listening to Circulation On The Run. Join us again next week.

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