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Circulation on the Run


Dec 5, 2022

This week, please join author Sean Pokorney and Associate Editor Shinya Goto as they discuss the article "Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial."

Dr Carolyn Lam:              

Welcome to Circulation on the Run, your weekly podcast summary and Backstage Pass of the journal and its editors. We're your cohost. 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, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting topic. In patients that have end stage renal disease that require dialysis, questions emerged should we anticoagulate them to prevent stroke, but of course, there's a risk of excess bleeding. Well, this feature discussion today is a study comparing apixaban and warfarin for anticoagulation in exactly this patient population. But before we get to those results, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?

Dr Carolyn Lam:              

Absolutely, Greg. So my first paper is a pre-specified analysis of the Paradise MI trial and knowing you'll likely ask me what that was about, Greg, at least to summarize for everyone, the Paradise MI trial compared sacubitril/valsartan with ramipril and its effect on reducing heart failure events after an MI in more than 5,600 patients with an acute myocardial infarction complicated by LV systolic dysfunction, pulmonary congestion, or both. Now in today's paper, what Dr. Mehran and colleagues found was that among patients with a recent AMI and LV systolic dysfunction, heart failure are both, sacubitril/valsartan decreased the risk of coronary related events by 14% as compared with ramipril over a median follow-up of 22 months. The reduction in coronary events occurred with a favorable safety profile.

Dr Greg Hundley:           

Wow, Carolyn, very interesting. Another indication perhaps for sacubitril/valsartan, especially relative to ACE inhibitors. So what does this mean for us clinically?

Dr Carolyn Lam:              

Well, the results really cause us to consider if in addition to antiplatelets and lipid lowering therapies, sacubitril/valsartan may be explored as a potential agent to mitigate the residual risk in survivors of AMI. Of course, dedicated studies are necessary to confirm this finding and elucidate its mechanism.

Dr Greg Hundley:           

Oh, very nice, Carolyn. Well, my first paper comes to us from the World of Preclinical Science and Carolyn, this study evaluated the scavenger receptors stabilin-1 and stabilin-2, proteins that are preferentially expressed by liver sinusoidal endothelial cells. Now, they mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. And studies suggest that stabilin-1 and stabilin-2 may impact atherosclerosis. So in this study, the investigative team led by Professor Cyrill Géraud from the University Medical Center and Medical Faculty in Mannheim, Heidelberg comprehensively studied how targeting stabilin-1 and stabilin-2 affects atherosclerosis.

Dr Carolyn Lam:              

Huh. All right, nicely explained. And so what did they find, Greg?

Dr Greg Hundley:           

Right, Carolyn. So inhibition of evolutionary conserved class H scavenger receptors, stabilin-1 and stabilin-2, reduced aortic plaque burden in preclinical models and athero protection was mediated likely through down regulation on transcriptional factor ERG1 in monocytes by multifaceted plasma protein changes. And then finally, Carolyn transforming growth factor beta induced periostin, reelin, and they are novel ligands of stabilin-1 and stabilin-2 and are implicated in the development of atherosclerosis.

Dr Carolyn Lam:              

Okay. Wow. Could you give us a take home message, please Greg?

Dr Greg Hundley:           

Right. Carolyn, I knew you had asked me this. So here we go. Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies provide a novel approach for the future treatment of atherosclerosis. And in the future, perhaps the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients.

Dr Carolyn Lam:              

Wow. Thanks Greg. My next paper is a true story of discovery. Now I could ask you what you know about the condition hypertension with brachydactyly type E... Greg, I love that expression. I wouldn't be able to answer that too. So let me tell you the story. So hypertension with brachydactyly type E is an autosomal dominant Mendelian disease resembling essential hypertension. Untreated patients die of stroke by the age of 50 years. Now, these authors had previously demonstrated a gain of function phosphodiesterase 3A gene mutations that caused the condition by increasing peripheral vascular resistance.

They studied a large family with the condition earlier and were puzzled that cardiac hypertrophy and heart failure did not occur despite the decades of hypertension. And so they hypothesized that in the heart, this phosphodiesterase 3A or PDE3A mutations could be protective. Isn't that neat? And so corresponding authors, Doctors Bader, Klussmann, Bähring and Hübner, all from the Max Delbruck Center for Molecular Medicine in Berlin, Germany. So they studied new patients as well as CRISPR-Cas9 engineered rat models of this condition of hypertension with brachydactyly type E. And they comprehensively phenotyped all of them with the human induced pluripotent stem cells carrying these PDE3A mutations as well. So analyzing all of this from cells to new patients to CRISPR-Cas9 models.

Dr Greg Hundley:           

Wow, Carolyn, what an interesting story. So what did they find?

Dr Carolyn Lam:              

So while in vascular smooth muscle, the PDE3A mutations caused hypertension, in the hearts, they conferred protection against hypertension-induced cardiac damage, hypertrophy and heart failure. The mechanism involved long-term adaptations of mRNA and protein expression as well as calcium cycling. Non-selective PDE3A inhibition was a final short term option in heart failure treatment to increase cardiac cyclic AMP and improve contractility. So the data argued that mimicking the effect of PDE3A mutations in the heart rather than non-selective PDE3 inhibition was cardioprotective in the long term. And these findings could indeed facilitate the search for new treatments to prevent hypertension-induced cardiac damage. This is discussed in a really lovely editorial by Dr. Chiong, Houslay, and Lavandero.

Dr Greg Hundley:           

Very nice, Carolyn. Wow. What another... we have such great articles from the World of Preclinical Science. Beautiful description as well. Well, we have some other articles in the issue, particularly from the Mailbag. And we have a Research Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI in a pre-participation cohort of Young Asian males with T-Wave inversion.”

Dr Carolyn Lam:              

Interesting. There's an exchange of letters between Dr. Xu and Huang regarding the article associations of dietary cholesterol, serum cholesterol and egg consumption with overall and cause-specific mortality with a systematic review and updated meta-analysis. There is a Perspective piece by Dr. Marcus on Smart watch detected atrial fibrillation, the value in positive predictive value. Isn't that interesting? And now onto that very, very important question of anticoagulation in patients with kidney disease. Can't wait. Let's go, shall we?

Dr Greg Hundley:           

You bet. Carolyn. Welcome listeners to our December 6th feature discussion. And we have with us today Dr. Sean Pokorney from Duke University in Durham, North Carolina, and our associate editor, Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome gentlemen. Well, Sean, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Sean Pokorney:        

Yeah, absolutely. Thanks for having me to discuss the renal AF trial. And so I would say that the background information to the study was that we know that atrial fibrillation is an incredibly common condition in patients with chronic kidney disease. And the decision of anticoagulation in patients with end-stage kidney disease, on hemodialysis is really quite complex because these patients are at high risk for stroke and they're at high risk for bleeding. There are concerns with warfarin around calcific uremic arteriolopathy or calciphylaxis and there have been some data including from the original Aristotle trial that apixaban was even more favorable in terms of bleeding reduction relative to warfarin in patients with more advanced chronic kidney disease.

Although patients with creatinine clearance less than 25 were excluded from Aristotle and really all patients with endstage kidney disease on hemodialysis have been excluded from all trials of atrial fibrillation in the past. And so we really wanted to evaluate the safety of apixaban versus warfarin in patients with end-stage kidney disease, on hemodialysis. And the hypothesis was that apixaban was going to be non-inferior to warfarin with respect to safety in terms of major or clinically relevant, non-major bleeding in these patients with atrial fibrillation and end stage kidney disease on hemodialysis.

Dr Greg Hundley:           

Thanks so much, Sean. And you've mentioned the renal AF trial. So could you describe for us, for your, I guess, substudy, what was the study population? Who did you include and describe for us also your study design?

Dr. Sean Pokorney:        

Yeah, absolutely. So the trial included patients who had end-stage kidney disease, and/or on hemodialysis, as well as having concomitant atrial fibrillation. And the patients had to have a CHA-VASc score greater than equal to two. All of the patients had to be on hemodialysis for at least three months. So these were chronic hemodialysis patients. And the study design was an open label randomized trial that was 1:1 randomization between apixaban and warfarin with blinded outcome evaluation. And again, the primary endpoint of the study was major or clinically relevant non-major bleeding based on ISTH definitions. And there were secondary endpoints looking at stroke, systemic embolism, death, medication adherence, and I think a really important sub-study looking at PK data. And the goal was to have 50 patients where we included PK data that was going to more represent what chronic apixaban dosing data would look like in these patients with end-stage kidney disease on hemodialysis.

And originally the goal of the trial was to include over 700 patients. Originally we were trying to include 762 patients based on our initial power calculations to achieve true non-inferiority. Unfortunately, the trial enrollment was low and so the trial was ultimately stopped prematurely at 154 patients, although we were able to include the original targeted 50 patients in the PK substudy. The dosing that we used in the renal AF trial was 5 mg of apixaban twice daily unless patients had a second dose-reduction criteria in addition to chronic kidney disease. So the fact that they had end-stage kidney disease and were on hemodialysis counted as one dose reduction criteria and patients that were under 60 kilograms or less were 80 years of age or older, who had then a second dose-reduction criteria were treated with the 2.5 mg twice daily dosage. And this was important to note because this is different than the dosage that was used in the AXADIA-AFNET trial.

Dr Greg Hundley:           

Very nice. And so Sean, what did you find?

Dr. Sean Pokorney:        

Yeah. So again, a lot of this data is really exploratory because of the limited sample size, we weren't really able to definitively conclude anything about the major or clinically relevant non-major bleeding rates. I would say that some of the key findings that we saw was that there were high rates of major or clinically relevant non-major bleeding in both arms of the trial and one year bleeding event rates were 25% in the warfarin arm and 31% in the apixaban arm. And again, there was no statistically significant difference, although again, this is really exploratory. I would say that some of the other interesting findings that we saw was that there were very low rates of ischemic and hemorrhagic stroke in this patient population. Again, there were 82 patients randomized to apixaban, 72 patients randomized to warfarin. And there was a difference in the randomization because of the stratification by site that was performed with the randomization.

And so within the 82 patients that were randomized to apixaban, the patients, there was one ischemic stroke and one hemorrhagic stroke. There were no hemorrhagic strokes in the warfarin population and two ischemic strokes. Another key finding was the high rates of mortality in this patient population. So 26% of the apixaban patients experienced a mortality event, 18% in the warfarin arm. So again, the mortality rates in these patient populations were extremely high. I would also emphasize some of the data from the PK analysis. So we looked at the PK analysis in two different ways. For the patients that were treated with the 5 mg dose of apixaban, the PK data showed that there was consistent overlap in the steady state concentration at one month compared to patients in the Aristotle trial that had really mild to moderate, moderate to severe and severe chronic kidney disease.

And so there was a consistent overlap in those steady state concentrations between the end-stage kidney disease population on hemodialysis and the chronic kidney disease population who benefited from a apixaban in the Aristotle trial. Similarly, in the 2.5 mg apixaban dose, the patient who had a second dose reduction criteria in addition to chronic kidney disease, those patients had consistent steady state concentrations of apixaban relative to patients with mild to severe chronic kidney disease.

Dr Greg Hundley:           

Very nice. Well thank you so much, Sean. And listeners, now we're going to turn to our associate editor, Dr. Shinya Goto. Shinya, can you, sort of, highlight for us some of the interesting findings that you see from these study results that Sean just presented?

Dr. Shinya Goto:             

Thank you, Greg. Thank you, Sean for your wonderful summary of your study. We had a great discussion with an editor for this paper. As Sean pointed out, this is a kind of underpowered trial or just terminated early, hypothesis was not tested in the trial. But this population of patient clearly needs a real-world clinical trial, patient with atrial fibrillation, end-stage kidney disease, on hemodialysis; things a clinician could do. In some country, nephology society defined warfarin contraindicated in this population. As Sean pointed out, whether the development of this trial include this high-risk population patient. So we had a discussion whether the underpowered trial provided something or nothing may be better than something just provided here. Our consensus finally reached was, this limited trial still provide something like, you have to make a decision to use the anticoagulation. I mean, that the apixaban might be still used due to the PK data. That is the kind of interesting point of this trial.

Dr Greg Hundley:           

Very nice Shinya. Well, Sean, turning back to you and Shinya with that nice lead in really, Sean, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Sean Pokorney:        

Yeah, absolutely. I think this is a challenging patient population to study. And again, our trial, the renal AF trial stopped early. Unfortunately, the AXADIA-AFNET 8 study also stopped early, which was also looking at apixaban versus warfarin outside the US and Europe. And so again, it is a challenging patient population to study. But again, I also think it's a really important population to study because one of the main unanswered questions in this population is whether or not they should receive anticoagulation. And so I think that ultimately more work and additional studies trying to determine whether or not these patients truly benefit from anticoagulation or stroke prevention, I think is really one of the critical directions that we need to take the field in.

Dr Greg Hundley:           

And Shinya, do you have anything to add?

Dr. Shinya Goto:             

Well, I fully agree with Sean. I mean, this is a very challenging area and still raising the question whether anticoagulation is necessary or not by your study. Maybe next generation oral anticoagulant such as Factor XI inhibitor that is more elevated to contact pathway may be beneficial. So we really need a good clinical study in this very important and known answered area.

Dr Greg Hundley:           

Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney from Duke University in Durham, North Carolina and our own associate editor, Dr. Shinya Goto from Tokai University in Japan for bringing us the results of this randomized open-label trial of apixaban versus warfarin in patients with chronic kidney disease on hemodialysis, revealing high rates of bleeding in both groups, but due to low enrollment, was unable to identify its non-inferiority endpoint. It's important to note, however, as both our author and editorialists have identified further research is really needed in this area to really examine the efficacy of anticoagulation for stroke prevention in this high-risk patient population.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.