Oct 25, 2021
Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials."
Dr. Carolyn Lam:
Welcome to circulation on the run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts; 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. Well, Carolyn, this week's feature, a couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets.
Dr. Greg Hundley:
This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives.
Dr. Carolyn Lam:
Ooooh, You so got my attention, Greg, a very important topic and so, what did they find?
Dr. Greg Hundley:
Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings.
Dr. Carolyn Lam:
Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes.
Dr. Greg Hundley:
Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find?
Dr. Carolyn Lam:
Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention.
Dr. Greg Hundley:
Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR.
Dr. Carolyn Lam:
Oh, very interesting. And what were the results?
Dr. Greg Hundley:
An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability.
Dr. Carolyn Lam:
Very nice, important stuff.
Dr. Carolyn Lam:
Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice.
Dr. Greg Hundley:
Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia.
Dr. Greg Hundley:
Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial?
Dr. Carolyn Lam:
Let's go Greg.
Dr. Carolyn Lam:
Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper,
Dr. Jonathan Newman:
Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD.
Dr. Carolyn Lam:
Great, thanks for lining that up so nicely. So what,
Dr. Jonathan Newman:
So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up.
Dr. Jonathan Newman:
And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that.
Dr. Carolyn Lam:
I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts.
Dr. Sandeep Das:
Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes.
Dr. Sandeep Das:
And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper.
Dr. Sandeep Das:
I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials.
Dr. Jonathan Newman:
It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested.
Dr. Jonathan Newman:
And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design.
Dr. Carolyn Lam:
Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh?
Dr. Jonathan Newman:
Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world.
Dr. Jonathan Newman:
So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials.
Dr. Carolyn Lam:
Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan?
Dr. Sandeep Das:
Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management.
Dr. Sandeep Das:
And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can
Speaker 3:
Love it, Jonathan.
Dr. Jonathan Newman:
Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals.
Dr. Jonathan Newman:
And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge.
Speaker 3:
Thanks so much, Jonathan, and thank you Sandeep for joining us today.
Speaker 3:
And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. 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 visit AHJjournals.org.