Mar 28, 2022
This week, join authors Steven Lubitz and Associate Editor Mark Link as they discuss the article "Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF 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 co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Huntley, Associate Editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Well, guess what we have for the featured discussion today, Greg. It's about screening for atrial fibrillation in older adults at primary care visits. Very, very important topic. And what we'll be looking at is the vital AF randomized control trial. Ooh, we're going to keep everyone in suspense here as we carry on and discuss today's papers. Can I start?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
Alright. This first paper is about infective endocarditis. Now, we know that cardiac surgery often represents the only treatment option in patients with infective endocarditis. However, infective endocarditis surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. So, authors Dr. Doesnst from Friedrich Schiller University of Jena in Germany, and colleagues, decided to investigate the impact of hemo absorption during infective endocarditis surgery on post-operative organ dysfunction.
This multicenter, randomized, non-blinded controlled trial assigned 288 patients undergoing cardiac surgery for infective endocarditis to hemo absorption, which is integration of cytosorb to the cardiopulmonary bypass or control. The primary outcome was defined as the difference between the mean total postoperative sequential organ failure assessment score, calculated maximally to the ninth postoperative day, and the difference with the basal score. Secondary outcomes were 30 day mortality, durations of mechanical ventilation, basal presser and renal replacement therapy. Cytokines were also measured in the first 50 patients.
Dr. Greg Hundley:
Interesting study, Carolyn. Wow. So, what are the results?
Dr. Carolyn Lam:
Yes, this trial involved a lot of work and results showed, however, that there was a failure to demonstrate a reduction in postoperative organ dysfunction, 30 day mortality, or any of the clinically relevant secondary outcomes through intraoperative hemo absorption. Although hemo absorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcomes.
Dr. Greg Hundley:
Great description, Carolyn. Well, my first paper comes to us from the world of preclinical science. And Carolyn, the ascending thoracic aorta, site of aneurysm formation, is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field, or the cardiac neural crest. Second heart field derives cells, populate areas that coincide with the spatial specificity of thoracic aortopathies that are often associated with aneurysms. And so, this study, led by Dr. Alan Daugherty, from the University of Kentucky. Its purpose was to determine whether and how second heart field derived cells contribute to as sending aortopathies.
Dr. Carolyn Lam:
Wow, an important topic, Greg. What did the authors find?
Dr. Greg Hundley:
Okay. So, Carolyn, first, ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin 2 infused mice. And so, the investigators found several things. First, second heart field derived smooth muscle cells and fibroblasts associate with angiotensin 2 induced aortic pathologies. Second, angiotensin 2 induced a distinct fibroblast sub-cluster that was less abundant for messenger RNAs related to major extracellular components and TGF beta-ligands and receptors, but more abundant for proliferative genes.
Third, TGFBR2 deletion in second heart field derived cells were embryonically lethal, with significant dilatation of the outflow tract in the mice. And finally, second heart field specific deletion of LRP1 led to aortic pathologies in mice, supporting the importance of second heart field derived cells in maintaining ascending aortic wall integrity.
Dr. Carolyn Lam:
Wow. Could you just sum up the clinical implications for us, Greg?
Dr. Greg Hundley:
Well, Carolyn, I knew you were going to ask me that. So, these results indicate that heterogeneity of the embryonic origins of smooth muscle cells and fibroblasts contributes to complex mechanisms of vasculopathy formation, which should be considered when investigating the pathogenesis of thoracic aortopathies.
Dr. Carolyn Lam:
Wow, thanks Greg. Well, my next study is also a translational study, and this one provides a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type one diabetes. So, this is from Dr. Biddinger from Children's Hospital Boston and colleagues. In order to define the mechanisms by which insulin controls plasma cholesterol levels, the authors knocked down the insulin receptor, FOXO1, and the key bioacid synthesis enzyme, CYP8B1, in mice. They measured bioacid composition, cholesterol absorption, and plasma cholesterol. In parallel, they measured markers of cholesterol absorption and synthesis in humans with type one diabetes treated with ezetimibe and statins in a double blind crossover study.
Dr. Greg Hundley:
Oh, wow, Carolyn. So, experiments in both animal models and in human subjects. So, what did they find?
Dr. Carolyn Lam:
Insulin, by inhibiting FOXO1 in the liver, reduces 12 alpha hydroxylated bio acids, reduces cholesterol absorption and reduces plasma cholesterol levels. Thus, type one diabetes leads to a unique set of derangement in cholesterol metabolism with increased absorption rather than increased synthesis. These derangements are reversed by ezetemibe, which is a cholesterol absorption inhibitor, but not simvastatin, which is a cholesterol emphasis inhibitor. So, taken together, these data suggest that a personalized approach to lipid lowering in type one diabetes may be more effective, and highlight the need for further studies specifically in this group of patients.
Dr. Greg Hundley:
Nice, Carolyn. Well, we've got some other really interesting or articles in the issue. And first, from the mail bag, there's a Research Letter from Professor Bers, entitled "Empagliflozin Reverses Late Sodium Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murray Model of Heart Failure with Preserved Ejection Fraction." Carolyn, there's another research letter from Professor Shu entitled, "Activation Of INKY Cells at the Maternal Fetal Interface that Predisposes Offspring to Cardiac Injury." Also, there's a really nice, in depth article entitled, "Takasubo Syndrome Pathophysiology Emerging in Concepts and Clinical Implications." And it's from Dr. Trisha Singh.
Dr. Carolyn Lam:
Nice. We also have an ECG challenge by Dr. Mugnai on “A Tachycardia in Disguise” and a Perspective piece by Dr. Alexander on “Equipoise in Clinical Trials: Enough Uncertainty [but] in Whose Opinion?” Isn't that interesting? Wow, thanks, Greg. Now, though, let's go on to this super exciting feature discussion on screening for atrial fibrillation in older adults' primary care.
Dr. Greg Hundley:
You bet.
Well, listeners, we are here for the feature discussion, now, on this March 29th issue. And we have with us Dr. Steve Lubitz, from Mass General and Boston, and our own associate editor, Dr. Mark Link, from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen.
So, Steve, we're going to start with you. Can you describe for us some of the background information that went into the construct of your study, and then what was the hypothesis that you wanted to address?
Dr. Steven Lubitz:
Sure. Well, thanks for the opportunity to talk with you today about our work. So, as we know, AFib is a common and more bitter arrhythmia. And the first manifestation of AFib can be stroke in a substantial number of individuals. Strokes from atrial fibrillation or debilitating, but they can be prevented using oral anticoagulants if we know who has atrial fibrillation.
But atrial fibrillation can be a symptomatic and it's possible, therefore, that screening pre-AFib could lead to new diagnoses and ultimately improve outcome by enabling stroke prevention. Point of care screening for AFib has been embraced by some guidelines for individuals age 65 or older, such as those in Europe, and mobile technology has now evolved and enables rapid mask screening using handheld ECGs, single lead ECGs, which obviates the need and expense of performing 12-lead ECGs to screen for AFib.
Nevertheless, though, some guidelines have suggested that data are insufficient to recommend screening AFib using ECGs, such as those from the United States Preventative Services Task Force. We tested whether screening individuals age 65 or older at the time of a primary care clinic visit using a single lead ECG would lead to an increased rate of detection of AFib in contemporary United States practices.
Dr. Greg Hundley:
Very nice. And so, maybe describe for us this task force, and also what was your study design and, again, your study population?
Dr. Steven Lubitz:
Sure. So, specifically our study design, we performed a cluster randomized control trial in which primary care practice clinics were randomized to the screening intervention or to usual care, and patients aged 65 or older arriving for a primary care visit with their provider were eligible for participation. Patients were offered screening by practiced medical assistants at the time of their vital sign assessments, and screening was performed, if they consented, within a live core cardio mobile single ECG device, which was affixed to an iPad and stationed in the clinic.
The results of the screening were made available to the providers at the time of the visit, and then the provider was able to make any and all decisions about subsequent management, confirmation or treatment. The primary outcome was a new diagnosis of Afib made in the medical record at one year following the start of the screening intervention, and the outcome was ascertained using the electronic health record and then manually adjudicated. We powered the study to detect a difference of nearly 0.5% in the rate of atrial fibrillation diagnoses at 12 months between the screening and usual care arms.
Dr. Greg Hundley:
And how many patients did you enroll? And then what were your study results?
Dr. Steven Lubitz:
Well, eight practices were randomized to the screening arm and eight practices to the usual care arm. And in total, that equated to about 15000 patients without a history of atrial fibrillation in the screening arm and 15000 patients in the control arm without a history of atrial fibrillation. The mean age was about 74, about 60% were female, 82% were white. And the mean chad-vad score was 3.4.
We observed several main findings. The first is that, of the individuals in the screening arm, 91% were screened at least once. And this is the largest point of care screening study to date. The rate of screening in the intervention arm was substantially greater than any other contemporary trial, point of care, single ECG screening. We think that high rate of compliance with the intervention reflects patient enthusiasm for screening and a widespread feasibility of incorporating single ECGs into the routine vital sign practice workflow.
Secondly, the primary endpoint, however, incidence of new AFib diagnoses at 12 months, was 1.72% in the screening arm, and 1.59% in the usual care arm, which equates to a risk difference of .13%. That was not statistically significant in the overall sample. We observed a substantial difference in new AFib diagnoses among those aged 85 or older in pre-specified subgroup analyses, 5.56% in the screening arm and 3.76% in usual care arm, which corresponds to a risk difference of 1.8%, where a number needed a screen of about 55, raising the possibility that point of care single ECG screening among the oldest and highest risk individuals might be effective. But this finding warrants future study.
Third, we observed a shift in the location of diagnosis. So, they fit with a higher likelihood of diagnosis at a primary care practice encounter in the screening arm, as compared to the usual care arm, which is as expected. And the implications on downstream management pathways, cost of care, other downstream work flows is unknown at the moment.
And lastly, we observed it in anticoagulation use was high, even among those with AFib diagnosed in the screening arm, which is a reassuring finding, suggesting that clinicians recognized that AF detected using this single lead point of care screening is likely to represent high burden, persistent AF that carries a substantial risk of stroke.
Dr. Greg Hundley:
Very nice. Well, Mark, I know you review many papers for us here at Circulation. What attracted you to this particular paper?
Dr. Mark Link:
This issue of point of care screening for AFib is a very hot topic. We all know that clinically diagnosed AFib carries with it a high risk of stroke, but what we don't know is incidentally found Afib, or nonclinically found Afib, what does that mean? This was one of the largest, if not actually the largest, study of point of care screening. And the i-cors are a very accurate device, or reasonably accurate device. So, we thought it's an important contribution to the literature. I think it surprised the authors, as well as us, there wasn't a difference in the diagnosis of AFib between the two arms. I think all of us would've expected to see that. But we're still learning a lot about point of care screening, and we're not to the point where we know what to do yet.
Dr. Greg Hundley:
And Mark, what are some of your thought? Steve raised the point that, in that subgroup, greater than age 85, any additional insights there?
Dr. Mark Link:
Yeah. I think that, if you can enrich your group with people that are more likely to have AFib, and the older you get, the more likely you are to have AFib, you are more likely to find Afib. But then treating people over age 85 also becomes a little bit riskier, with both anticoagulants and antirhythmic drugs and ablation.
Dr. Greg Hundley:
Great points. Well, Steve, coming back to you, what do you see as the next study to be performed, really, in this sphere of research?
Dr. Steven Lubitz:
Thanks. I think I proposed two additional lines of inquiry. At first, I think our hypothesis generating observation to the point of care screening with a single EDCG can lead to higher rates of AFib detection among the oldest individuals, age 85 or older, with a small number needed to screen warrants, replication, and the downstream implications of that on stroke and bleeding merit further evaluation.
I think secondly, given the proliferation of wearable technology, future studies should examine the effectiveness of detecting perccismal atrial fibrillation for preventing downstream adverse events, including stroke. This point of care screening is likely to detect the highest burden persistent forms of atrial fibrillation in contrast to some of the wearable technology, like consumer wearable technology, that might detect paroxysmal atrial fibrillation, more commonly.
Dr. Greg Hundley:
Ah, great point. And Mark, how about you? Anything to add? What future study do you see needs to be performed in this space?
Dr. Mark Link:
It's clear from a number of studies that the longer that you monitor someone, the more likely you are to get a diagnosis of AFib. And that's pretty clear. This was a 30 second monitor. We have a number of studies that have shown two week and ILS monitoring is far more likely to get a diagnosis of AFib. But what we don't know is, if making that diagnosis of AFib makes any difference on ultimate outcomes. That's the studies that we need to see, is does treatment of incidentally found AFib improve clinical care.
Dr. Greg Hundley:
Very good. Well, listeners, we want to thank Dr. Steve Lubitz from Mass General in Boston, and also Dr. Mark Link from UT Southwestern in Dallas, bringing us results from this study indicating that screening for atrial fibrillation using a single lead EKG at a primary care visit did not affect new atrial fibrillation diagnoses among those that were aged 65 years or older. There was, perhaps, a difference in those aged greater than 85 years, but more research is to come in that space. And, of course, looking for peroxisomal AFib with handheld devices is another area you yet to be investigated.
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.