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Circulation on the Run

Feb 5, 2018

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. In today's feature discussion, we are talking about external validation of the DAPT score, a discussion that's going to take us all the way to east Asia, but for now, here are your weekly summaries.

                                                In this week's journal, two studies are presented which compare ductal stenting to surgical shunts in the current era of ductal dependent pulmonary blood flow. As background, infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt between the subclavian artery and either pulmonary arteries. This modified Blalock–Taussig shunt allows progress through early life to an age and weight at which repair or furthermore stable palliation can be safely achieved. However, these modified Blalock–Taussig shunts continue to present concern for post-procedure instability and early mortality.

                                                Duct stenting has emerged as an alternative with potential for greater early stability and improved survival. In the first study, first and corresponding author Dr. Bentham from Yorkshire Heart Centre reviewed data from the National Congenital Heart Audit, comparing the outcomes of 171 neonates who underwent a modified Blalock–Taussig shunt and 83 who underwent attempted ductal stenting, all in the setting of duct dependent pulmonary blood flow between 2012 and 2015. They found that stenting the arterial duct was preferable over the modified Blalock–Taussig shunt in terms of survival to next stage surgery, early post-procedure hemodynamic stability and shorter intensive care and hospital stay. There was a high failure rate both early, with the inability to stent the duct and late, with a greater need for re-intervention on the stented duct compared to the surgical shunt.

                                                The second study originated from four North American pediatric cardiology centers representing the Congenital Catheterization Research Collaborative. First and corresponding author, Dr. Glatz from Children's Hospital of Philadelphia performed a retrospective cohort study reviewing all infants with ductal dependent pulmonary blood flow under a year of age, having either a ductal stent or a modified Blalock–Taussig shunt between 2008 and 2015. Although the observed risks of the primary outcome of death or unplanned re-intervention to treat cyanosis was higher in the surgical shunt group, there was no significant difference between groups after adjusting for patient level factors. Furthermore, after adjusting for patient factors, other outcomes favored the stent group, including fewer procedural complications, shorter intensive care unit length of stay, less frequent need for diuretics and larger and more symmetric pulmonary arteries at last follow up.

                                                These companion papers are discussed in an elegant editorial by Drs. Benson and Van Arsdell from Hospital for Sick Children in Toronto.

                                                The next study tells us that there may be a higher risk of vascular dementia in patient who survive a myocardial infarction. First and corresponding author, Dr. Sundbøll from Aarhus University Hospital in Denmark performed a nationwide, population based study including almost 315,000 patients with myocardial infarction and found that the risk of vascular dementia was higher compared to a matched general population comparison cohort. The risk of vascular dementia was incrementally higher in patients who suffered stroke or developed severe heart failure during the first year after myocardial infarction and in patients who underwent coronary artery bypass grafting. There was no association with all caused dementia, Alzheimer's disease or other dementia sub-types. Take home message is that among one year survivors of myocardial infarction, attention should be placed to persistently higher risk of vascular dementia.

                                                The next study identifies a novel mechanism whereby the RNA binding protein, fragile X mental retardation autosomal homologue one or FXR1, directly regulates gap junction remodeling, leading to dilated cardiomyopathy. Co-first authors Drs. Chu and Novak, corresponding author Dr. Gregorio and colleagues from University of Arizona studied human left ventricle dilated cardiomyopathy biopsy samples as well as mouse models of dilated cardiomyopathy. They found that FXR1 expression was significantly increased in human and mouse dilated cardiomyopathy. Up regulation of FXR1 in the heart altered the location and distribution of gap junctions, subsequently leading to ventricular tachycardia in mice.

                                                Mechanistically, FXR1 associated with intercollated discs and directly interacted with integral gap junction proteins to regulate their expression in cardiomyocytes. Finally, loss of FXR1 in the heart led to dilated cardiomyopathy. Together, these results provide a novel function of FXR1, namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. Thus, the authors concluded that FXR1 may be a promising target for therapeutic strategies to improve gap junction function in dilated cardiomyopathy.

                                                Well everyone, that wraps it up for our summaries. Now for our feature discussion.

                                                The dual anti-platelet therapy or DAPT score is widely used everywhere to estimate bleeding versus ischemic risk in patients undergoing percutaneous pulmonary intervention. However, very few studies have provided external validation of its utility. Well we have a very important paper in this week's journal that addresses just that in a Japanese population. So pleased to have with us the corresponding author, Dr. Takeshi Kimura from Kyoto University Graduate School of Medicine. Not just him, but also the editorialist for this paper, Dr. Shinya Goto, also an associate editor of Circulation from Tokai University of Japan and last but not least of course, our dear Senior Associate Editor of Circulation, Dr. Laura Mauri from Brigham and Women's Hospital. What an important topic. Takeshi, would you mind to please tell us about your study to start?

Dr Takeshi Kimura:          Actually we thought about the utility of the DAPT score provided from the DAPT study in Japanese patient population. In a full cohort of three studies that are conducted in Japan, we compare the risks for ischemic and bleeding risks from 13 to 36 months after a PCI between patients with DAPT score (high-DS) and DAPT score <2 (low-DS) in patients in the Japanese population. We evaluated 12,223 patients. There were 1,344 patients with high DAPT score, 8,279 patients with low DAPT score. The cumulative incidence of primary ischemic end point myocardial infarction or stents from both is significantly higher in the high DAPT score group than in the low DAPT score group. 

                                                One of the cumulative incidence of the primary bleeding end point tended to be lower in high DAPT score than in the low DAPT score group, therefore the DAP score has successfully stratified ischemic and bleeding risks in Japanese patients. We've externally validated DAPT score successfully.

Dr Carolyn Lam:                Thank you so much Takeshi. Shinya, you wrote an excellent editorial to this paper. Could you let us know why it was so important to validate this in the Japanese population?

Dr Shinya Goto:                It's quite homogenous in one way and the other way in the world is heterogeneous. Some may say the risk of thrombotic and the bleeding event in Japanese or East Asia might be different from other regions of world. Dr. Kimura’s paper is the first validation of the DAPT score in the East Asian patient. Original attempts to study didn't include patients from East Asia. This is the real first validation of the DAPT score in that East Asian population. The world is quite homogeneous. It is very important message.

Dr Carolyn Lam:                Yes, yes, I agree. Could I just ask maybe a cheeky question. What would you have thought may be any differences?

Dr Shinya Goto:                Indeed, previous global trial and also global registry showed relatively low risk of ischemic event. Maybe not many of the US reader doesn't know we are using relatively low dose over anti-coagulant agent for preventing stent thrombosis. Dr. Kimura's paper provides very important insight. DAPT score is predictable for that event but even in the population with lower use of anti-coagulant agent like standard dose of prasugrel in Japan is just 3.75 milligram. Maybe that thrombogenicity in Japanese populations is lower as compared to the global population. Still that’s quite predictable for the ischemic event. That's very important message.

Dr Carolyn Lam:                I agree and I have to tell you, practicing in Asia too, I have a tendency to think the bleeding risk may be underestimated by existing scores. We also tend to use lower doses, so it's so important to show objective data such as these. Laura, what are your thoughts coming from the US?

Dr Laura Mauri:                 Well I think it's very important. I want to congratulate Takeshi, it's a wonderful study, very large randomized data set and very important. I think in the grand scheme of things we do randomized trials, we can't represent every single population in every study. The DAPT study was done in the US, Europe, as well as in Australia and New Zealand, but it's true. We weren't able to also include sites in Asia just from practical reasons. I think it's very exciting to see, looking at this question of the DAPT score in patients in Japan.

                                                I think in general, it matters a lot to understand the generalizability of our randomized trial results across different populations. I think Shinya's mentioned some of the important sources of variability. It may be this great interest in understanding genetics and how they relate in different populations, but there are also clear differences in medical practice across the world. Doing this type of study where one looks at different populations is quite important and I think it's also one of the reasons that circulation in terms of the editors are really seeking to expand the international scope of the randomized trials and secondary studies from randomized studies such as this that really impact patient care across the world.

Dr Takeshi Kimura:          I think one of the difference from the DAPT studies in this Japanese closed study is the proportion of the high DAPT score versus low DAPT score is a little bit different. In the Japanese study population, the low DAPT score patients are dominant and also ischemic event risk are lower. However, the DAPT score clearly differentiates that, stratifies the bleeding and the ischemic risks so we should see both the bleeding and ischemic risk and also the difference of absolute event rates in each geographic ischemic population. I think it's important message from this paper.

Dr Carolyn Lam:                That is such a great point, Takeshi. In other words, there may be some heterogeneity around the world in baseline risks, as Laura said, baseline practice patterns and I'm talking about baseline both ischemic and bleeding risks. What your paper definitely shows is that the DAPT score however, performs similarly and as we've said so many times, that's such an important message. Shinya, what do you think? What's your message to all the audience out there in Japan and abroad?

Dr Shinya Goto:                As Takeshi told me and also how Laura pointed out, if we try to find the difference in the world, there is a difference and if we try to find the similarity, there is a similarity. Dr. Kimura paper shows similarity in the risk factor determining the ischemic and bleeding event. Matched, absolute event risk is low. Background medication is not the same. Majority of the patient taking [inaudible], 200 milligrams a day. [Inaudible] is a bad drug already in the world, but still in Japan, the doctor is still using. Clopidogrel, 75 milligram is also very widely used. The prasugrel dose is just 3.75 milligrams. That is different from the world. Ticagrelor with the dose similar to the world was not successful in the clinical trial in East Asia.

                                                There is a similarity and heterogeneity. Dr. Kimara beautifully demonstrated both in his registry.

Dr Carolyn Lam:                Indeed. Laura, looking at this now with these new data, do you think clinical trials should be done any different? Should we be doing multiple small trials maybe in different parts of the world now? Should we power trials to look at regional differences? This trial business is really hard, isn't it?

Dr Laura Mauri:                 That's a great question. It does come up practicality, whether we should do the same clinical trial in multiple different countries. I don't think it's the six answer, I think that as Shinya, I think, was alluding to, I think that patients responses worldwide are more similar than they are different. That doesn't mean when we plan our trials we shouldn't think about what the differences are and how they might impact the results and whether we might need to make confirmations across the world. I think this study is quite important because it finds the commonality across different populations even though there may be underlying differences that Takeshi mentioned in the baseline rate. I think a similar approach worldwide where we go in with a hypothesis about where things may be consistent or different to determine whether trials need to be replicated elsewhere is useful to have.

Dr Carolyn Lam:                Thanks so much, Laura. I don't think any of us could have said it better.

                                                Thank you all for joining me on the show today and thank you ladies and gentlemen throughout the world for listening in today. You've been listening to Circulation on the Run, don't forget to tune in again next week.