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Circulation on the Run

Mar 18, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and it's editors. We're your co-hosts. I'm Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences.

Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg.

Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.

                                                So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months.

Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to.

Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.

                                                Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise.

Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show?

Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.

                                                So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.

                                                So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together.

Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.

                                                Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.

                                                Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk.

Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks?

Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.

                                                So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.

                                                So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median.

Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels?

Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.

                                                Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space.

Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors.

Dr Carolyn Lam:                Yeah.

Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.

                                                So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored.

Dr Carolyn Lam:                Huh, interesting. So, what did they find?

Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.

                                                Interesting, Carolyn. Another role for iron in acute MI and more research to come.

Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?

                                                For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come?

Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.

                                                So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint.

Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results?

Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.

                                                And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well.

Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here?

Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.

                                                And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well.

Dr Carolyn Lam:                Bill, did you expect such remarkable results?

Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions.

Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this?

Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world.

Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others.

Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there?

Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program.

Dr Carolyn Lam:                Thank you so much for sharing that with us.

                                                Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.