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.
Dr Greg Hundley: And I'm Greg Hundley, associate editor and director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Dr Carolyn Lam: So, Greg, are we any closer to the holy grail of safe ED discharge for acute heart failure based on a risk score? Well, we're going to be discussing that coming right up after Greg and I share about the papers that we'd like to discuss today. Lovely issue, isn't it?
Dr Greg Hundley: Yup, and time to get your coffee and bring it up. My first paper, Carolyn, is from Michael Chu from London Health Sciences Center, and is really investigating the surgical management of thoracic aortic disease, and looking at the impact of gender or sex related differences. Sex related differences have not been thoroughly studied. This group looked at a total of 1653 patients, 30% were women, who underwent thoracic aortic surgery with hypothermic circulatory arrest between the years of 2002 and 2017 across Canada in 10 institutions.
Well, women underwent less aortic root reconstruction, including aortic root replacement, Ross procedures, or valve sparing root operations. But, even with less invasive, the women experienced higher rates of mortality, 11% versus 7%, stroke, and that composite of the thoracic surgeons' adverse events. On multi variable analysis, female sex or women was an independent predictor of overall mortality, stroke, and those comorbidities.
Dr Carolyn Lam: Greg, you know how much I love these papers, so I'm going to repeat that. You're saying the women received less ominous procedures and yet had worse outcomes, and this was independent of the clinical covariances, right?
Dr Greg Hundley: Absolutely. Putting all this together, women underwent thoracic aortic surgery a little bit older, and with larger index aortic aneurysm size than men. Intraoperatively, women undergo fewer concomitant procedures, such as the aortic root repairs, and things that you just mentioned. But nevertheless, women experience significantly worse outcomes identified as an independent predictor of mortality, stroke, and that composite endpoint for mortality, morbidity, after multi variable analysis.
What should we think about this? Well, sex specific considerations are important when considering thoracic aortic surgery and future research should focus on the development of a personalized approach to thoracic aortic surgery with respect to gender. For example, utilization of maybe lower size thresholds for women for aortic aneurysms should be considered, and for earlier interventions, and improved outcomes.
Carolyn, tell me about one of your papers.
Dr Carolyn Lam: All right, so I chose a paper looking at the stroke outcomes in the COMPASS trial. Now, let's remind everybody that the COMPASS trial, where patients with stable coronary artery disease or peripheral artery disease, and randomly assigned to receive aspirin 100 milligrams daily, rivaroxaban five milligrams twice daily, or the combination of rivaroxaban 2.5 milligrams twice daily plus aspirin. Patients requiring anticoagulation with a stroke within a month had a previous lacunar stroke or intracerebral hemorrhage were excluded.
Now, in the current paper, and this is from Dr Sharma from Population Health Research Institute, and their colleagues, basically they looked at a detailed analysis of the stroke by type, predictors, and anti-thrombotic effects in the key subgroups. They found that the combination of low dose rivaroxaban and aspirin prevented stroke and disabling stroke better than aspirin in patients without atrial fibrillation and with stable vascular disease, and without an increasing risk of hemorrhagic stroke; which is really important. This effect was consistent across subgroups of baseline risk, and particularly marked in those with a history of previous stroke.
Dr Greg Hundley: Carolyn, what about that rivaroxaban five milligrams twice daily alone?
Dr Carolyn Lam: There was no significant difference in the occurrence of stroke in the rivaroxaban alone group compared with aspirin. But all of this simply says perhaps low dose rivaroxaban and aspirin may be a really important new anti-thrombotic option for primary and secondary stroke prevention in patients with clinical stable atherosclerosis.
Dr Greg Hundley: Very interesting. I'm going to follow your lead and go into another sort of anticoagulant-related topic on iliofemoral deep vein thrombosis. This paper is by Suresh Vedantham from the Washington University of St. Louis.
Let's talk about just what is the definition? This is a DVT that involves the iliac and/or the common femoral vein with or without involvement of additional veins. It basically obstructs the outflow of the veins. These patients are phenotypically distinct from patients with cath or femoral popliteal DVT because that totally obstructs flow, and they have more frequent recurrence of venous thromboembolic events, and more frequent post-thrombotic syndrome. Well, that's a horrible condition because of that obstruction, it leads to calf muscle dysfunction, edema, subcutaneous fibrosis, tissue hypoxia, and ulceration.
Dr Carolyn Lam: Great background. What did this study show?
Dr Greg Hundley: This is a sub-study of the ATTRACT trial. The ATTRACT trial basically is looking at anticoagulation plus perhaps mechanical intervention, or direct catheter directed thrombolysis therapy versus just anticoagulation alone. This sub-study is 391 patients with acute DVT involving just the iliac or the common femoral veins, and following these individuals for 24 months to compare short and long-term outcomes.
What did the study show? Well, this interventional group did have a reduction in leg pain and swelling, and improvement in quality of life related to that lower extremity. But, no overall difference in overall quality of life, and very importantly, no difference in the occurrence of this post thrombotic syndrome.
Dr Carolyn Lam: That's kind of disappointing. I understand that the ATTRACT study is not the first to look at this, though. That was in an editorial discussing this. Could you tell us about that?
Dr Greg Hundley: Yeah, Carolyn. Jay Giri from University of Pennsylvania just had an incredible editorial. I think if you have an opportunity, listeners, to take a look at that, I highly recommend it. He reminded us of the CaVenT trial, which is basically performed as an open label randomized control trial of 209 patients across 20 hospitals in Norway.
What was different in the CaVenT trial is that at 24 months of follow up, the intervention with thrombolysis and systemic anticoagulation improved iliofemoral patency. It reduced the incidence of this post thrombotic syndrome. In ATTRACT, in this sub-study, it was intravenous thrombolysis, systemic anticoagulation, and mechanical intervention on the vein versus in the other study from Norway, CaVenT, just the inter vein thrombolysis and the systemic anticoagulation.
What Dr Giri points out is that maybe something related to intervention in that vein when you're stripping out thrombus, et cetera, are we damaging the veins in the vessel that prevents reflux, et cetera?
I think really moving forward, you're going to have to personalize this decision in individual patients until we have more data on this subject.
Dr Carolyn Lam: Great learning. I learned a lot from this next paper, too, because I actually chose a basic science paper. This is a paper that uncovers a new fine tuning factor that modulates myocardial infarction induced inflammation. That is a small GTPase called RhoE.
In this study, Drs Chang from Texas A&M University College of Medicine, and Song from Fuwai Hospital in Beijing used three genetic mouse model lines. Those are the global knockout, the cardiomyocyte specific RhoE heterozygous mouse, and the cardiomyocyte specific RhoE over expression mouse. With this combination, they showed that RhoE deficiency causes excessive inflammatory response in infarct animal heart, resulting in enlarged heart, decreased contractility, and increased mortality. The mechanism is that RhoE binds to P65 and P50, which impedes their dimerization and blocks these two proteins from nuclear translocation. Now, over expression of cardiac RhoE inhibits NF-κB, restrains post MI inflammation, and improves cardiac function and survival.
Importantly as you always say, Greg, there is human data. They found that the expression of RhoE was elevated in the infarct patient heart and that patients with a higher expression of RhoE exhibited a better prognosis and better cardiac function recovery.
Dr Greg Hundley: Carolyn, tell me a little bit about the clinical significance of this.
Dr Carolyn Lam: You just wanted to ask me a tough question. I can see it on your face. Basically, I think this is really exciting because RhoE may serve as a new potential biomarker for the assessment of myocardial infarction in patients, and manipulation of RhoE could be a potential therapeutic approach for MI. There.
Dr Greg Hundley: Very good.
Dr Carolyn Lam: That's all the time we have for our little discussion here. Now, let's go onto the feature paper. ...
Over 80% of emergency department patients with acute heart failure are admitted to the hospital. Now, contrast this with the fact that over 80% of all emergency department visits result in discharge. So, why is that many other emergency department based cardiovascular disease processes like for acute coronary syndrome have evolved from high rates of admission to timely and safe discharge whereas decision making in acute heart failure has not experienced a similar evolution. Do we need perhaps a better acute heart failure prognostic score that's validated?
Well, guess what? We're going to talk about this right now in our feature discussion, and a beautiful feature paper that we're so proud to have the corresponding author, Dr Douglas Lee from University of Toronto right here to discuss; along with the managing editor, Dr Justin Ezekowitz, who's associate editor from University of Alberta, and the editorialist, Dr Sean Collins from Vanderbilt University Medical Center. Welcome everyone, and Doug, please, could you just start by telling us about this great paper?
Dr Douglas Lee: We validated, and it's a tool, decision making tool, for acute heart failure patients in the emergency department. We, in this study, wanted to prospectively validate a decision making prognostic tool called the Emergency Heart Failure Mortality Risk Grade, or EHFMRG for short, to see how well it performed in the real world busy emergency department hospital setting.
We studied just under 2,000 patients who came to emergency departments at multiple centers, and asked physicians to rate their prognostic estimation of what's going to happen to that patient in the next seven days. We compared that with the EHFMRG model, which predicts outcomes of seven days and 30 days. We were very careful to ask physicians to provide their prognostic estimates. This is their intuitive guesstimation of the risk of the patient before calculating the score because we didn't want the physicians to be influenced by the score.
What we found was that when we looked at how well physicians' estimates performed, they actually performed quite well. The c-statistic for physician estimated risk was around .7, which is a reasonable discrimination. However, the physicians' estimates were not as good as the EHFMRG risk score, which had a C greater than .8. The mathematical model seemed to do better in terms of predicting what's going to happen to the patient than physicians' estimates.
Interestingly, when we combined the physicians' estimates with the EHFMRG risk score, the c-statistic improved by another 1%, so there's some additive value of having both factors combined.
The other interesting finding was that patients in the lowest risk groups had 0% mortality at seven days, and 0% mortality at 30 days. We may be able to identify, using the score, patients who have a very low risk of events in that seven to 30 day period after emergency department presentation.
Dr Carolyn Lam: Thanks so much, Doug. I have to tell you, I am a fan of the EHFMRG score. In fact, we're trying to study how well it performs in our local situation even here in Singapore.
Justin, you've been thinking a lot about this. I would love for you to share the reactions that we got when we discussed this among the editors.
Dr Justin Ezekowitz: We had a lot of good discussion about this from a number of different aspects. First, it's an in-practice assessment, a physician-based risk assessment, as we survey hundreds of physicians in the ER, which is a busy environment, and get these types of information. That's a very unique piece of this study where, in addition to the just under 2,000 patients and collecting the other data in a robust way, this really does have a potential to contribute to the literature.
A lot of the discussion was about how data rich this is, and that this is an area where unlike acute cardiovascular disease where there are good risk assessment tools and other therapies, it's a really need of a scoring system that was well validated, can be replicated, and both in clinical practice as well as in selective cohorts. Doug, my congrats to your and the other parts of the team that's helped put this together.
One of the questions that came up when we were discussing it was the risk textiles and buckets were very important for people to think about the very low risk, as you mentioned, 0% all the way up through much higher percents for seven day mortality, but how discrepant the risk was of the physicians versus the mathematical model; and a very good reminder of the inaccuracy of sometimes our assessments of risk in practice, especially in acute care.
I wonder if you could comment on what your fence was from the physicians who participated in the study, and then the data of those, the most striking findings of that piece about where physicians make judgements on risk in for that seven-day mortality. Just any comments you may have?
Dr Douglas Lee: We didn't know what to expect because there haven’t been many studies of this type before. What we found in our study was that physicians tended to overestimate the risk of lower risk patients. They thought bad things would happen to healthier patients, just to put it very simply. Physicians also underestimated the risk of the highest risk patients. They thought that the highest risk patients would do well.
We were surprised about that finding, but also, we were not surprised in the fact that it seems to explain some of our earlier findings that in our earlier work, we found that low risk patients are hospitalized, and we think it's probably that physicians are admitting those patients because they want to ensure that they're making a safe decision; and no harm will fall in the patient. Maybe physicians are erring on the side of admitting those patients, even though they know they're a little bit low risk.
At the other extreme, physicians underestimated risk in the highest risk patients. We think it might explain the observation that we made previously that sometimes high risk patients are discharged home, and they die at home after discharge. That may be because patients who look well to physicians, I think there's great value in the clinical experience of a seasoned physician looking at a patient and knowing that, that patient is sick or not sick. But in certain cases, patients may look relatively well, but their numbers would indicate that they're actually higher risk. I think it's that group where we found they're higher risk, but physicians thought that they were healthier than they were. It seems physicians' estimations really have great value, but it seems that they can be improved.
Dr Carolyn Lam: Sean, you discussed this beautifully in your editorial. Share with us your thoughts, and especially thoughts on the question you posed: are we any closer to the holy grail of safe emergency department discharge based on acute heart failure risk rules?
Dr Sean Collins: Doug, kudos to you. Nearly 2,000 patients, nine different hospitals, prospective data collection, as Justin said. I don't think this can be overstated. From a data cleaning perspective, this is truly a labor of love, and to get this done, congratulations to you and your team.
I think the most interesting part of this is this exact disconnect of patients look well who are high risk, and patients may look a little bit unwell who may be low risk, ironically. That's where a risk tool is much needed, as Carolyn said in her introduction to sort of change the dynamic of 80 to 90% of patients are admitted to the hospital. If we even chipped away at 10 to 15% to able to be discharged, it would be a huge win for partly for management for an emergency department perspective.
I think that the importantly, the next steps will be now looking at implementing this in some sort of a randomized manner, somewhat like what you did with asking physicians gestalt about what their level of risk is, but really finding out how does a physician gestalt when it comes to nuance and heart failure. A relative amount of congestion, even when the tool says the patient may be low risk, can they go home? I think that will be the crucial next step to find out how much does this augment and/or detract from physician decision making? We have a long way to go, as Carolyn said. It's just the complete opposite at almost every other disease process, including chest pain, from a discharge perspective. Even a little bit improvement would be great, so I'm looking forward to seeing the next steps, and I'm wondering what your thoughts are about the next steps, Doug.
Dr Douglas Lee: There's actually great value in physicians' clinical judgment. It's been, I think relatively understudied. I'm hopeful that future studies where decision tools or prognostic tools are validated, we can see more potentially, more comparisons with clinicians because we don't have a real great understanding, I think, of how doctors think, especially in an acute setting. More research in this area, I think would be really helpful, especially as we ... As more and more clinical decision tools being published, it would be great to see how well they hold up against good clinician judgment.
In terms of next steps and implementation, when we talk to our emergency colleagues, they have brought up an issue about it's great that patients are low risk, and that we could potentially discharge them from hospital; but where is the receptor to take that patient and to care for that patient once they've left the hospital? Are they going to get good care once they leave the hospital? Are there structures in place?
We're now embarking on testing this in the clinical trial where we will be comparing two strategies. The first strategy will be using the risk score at a hospital-wide level, and then discharging home patients who are in the lower risk categories, and having them follow up, and receive their care in a rapid ambulatory follow up clinic within two to three days after discharge from the emergency. This will be compared to the control, which is not using the risk score, and having usual follow up care. This trial is called the Comparison of Outcomes and Access to Heart Failure Trial, or the COAHFT trial. It is currently ongoing.
Dr Sean Collins: Great point, Doug. As Carolyn suggested with chest pain and heart failure as the interesting dichotomy is that unlike chest pain, when we safely rule somebody out and send them home, we're sort of done with that acute episode. Heart failure, it doesn't end. We've found that they're safe enough to go home, but now they need great collaboration and outpatient support with their heart failure provider, which may be as equally heavy lift as externally validating the EHFMRG score. You bring up a great point, which is we need to have outpatient follow up and collaboration for this to be successful. Thanks.
Dr Carolyn Lam: Awesome comments, guys. Could I switch tracks a bit and maybe just ask Justin to round up by sharing? Circulation, we get a lot of papers about risk scores and so on. There's a bit of fatigue, I think, about scores in all kinds of things. Now, could you maybe tell us, Justin, what makes us look at a paper twice, and in fact, feature this one with a good editorial? I mean it's clearly very clinically applicable. Could you share some thoughts there?
Dr Justin Ezekowitz: Yes, that's a great point. The things that make a risk score like this kind of elevated into kind of a circulation level of manuscript is A) the data quality has to be excellent. There has to be lots of completeness of data, but also capture of elements that we think are quite important. Two, the data science about how it's analyzed and put together, and interpreted, it has to be to the bar that we feel would be robust, and be able ... if somebody could repeat it and replicate it without an obvious challenge to the quality.
The third, I think is the clinical applicability. It's okay to write a data model and come up with all these great risk scores, but if they haven't been thought through about how either a patient will be seeing this, or clinicians behave, or the environment that it has to be deployed in that, that isn't necessarily going to be something that is going to be implemented. Then, the question is: why would somebody do the study in the first place?
Now, it's okay if somebody's forward thinking and saying, 'Look, EMRs are coming, or other EHRs around, so this could be implemented if there was enough impetuous and it's a good enough quality.' That's actually okay, but in the reverse where if you try to implement a model that is too complex, and it's in a hand-off to the environment, it just won't work. We just want to make sure people have thought that next knowledge translation and dissemination approach through.
The final part is things that have a very local impact are, that are very unique to the environment they're in, such as it only would work in your hometown or your own country because of some environment, that's okay. But under that, the much more global focus that, that is, it could be picked up and trans located to any major city, providence, state, or country, because vis vises are global. Those things have a much greater impact because the circulation leadership is global. The patients are global. The clinicians who care for them are also global. People are all looking for very similar situations and can adapt to their own environments.
Dr Carolyn Lam: Awesome, Justin. I don't think any of us could have said it better. Those are the reasons that we're so grateful that you publish with us, Doug. Thank you so much, Sean, for your excellent editorial, too.
Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
This program is copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. And I am so privileged to be joined by Senior Associate Editors whom I respect and admire so much. And they are Dr Biykem Bozkurt from Baylor College of Medicine and Dr Sana Al-Khatib from Duke University. And we have three woman discussing the Go Red for Women issue. Yes!
The current issue is the third Go Red for Women issue and boy, is it a bonanza issue. It tackles a wide spectrum of topics relating to cardiovascular disease in women, including prevention, risk stratification, myocardial infarction, pregnancy, heart failure, cardiac arrest, sudden cardiac death, and in so many wonderful formats; from original papers to systematic reviews, state-of-the-art papers, in-depth reviews, a research letter, and even frame of reference papers.
So, let’s get digging into this issue, shall we? And Biykem, we could start with you because I'd like to start with three original papers that really set the scene. The first discussed temporal changes and the very contemporary data from 2001 to 2016, describing cardiovascular risk factors and their treatment. And then the second focuses on young females with acute myocardial infarction. And the third on older women. Could you take us through these papers Biykem?
Dr Biykem Bozkurt: Lets first start looking at the sex differences through the Anne Haines Survey which enrolled more than 35000 patients. And they examined the trend all the way back from 2000 to 2016. Now the good news is the improvement in hypertension diabetes hyperlipidemia in woman were similar to men. So that's the good news. But BMI increased more in women than in men and overall, the ability to control blood pressure and diabetes hyperlipidemia appear to be a little bit better for women than in men.
But the concerning trend becomes apparent when we look at another paper that examined the twenty-year trend in young adults. Now, the first message is, and this is important for both genders, the proportion of the hospitalizations that are attributable to young patients, and young patients are defined as ages between 35 and 54 in this study, and this study was from Erik, increased from 1995 to 2014. So young patients appear to be having more in life compared to before, compared to 1990s and the 2000s. And that was actually partly due to the increasing prevalence of comorbidities, such as hypertension diabetes among young patients.
Now, interestingly among young patients, young women presenting with [inaudible] had a lower likelihood of receiving guideline directed therapy which, of course, sound familiar to our audience because we have the disparities of lower treatments and lower access to care in women with MI presentation compared to men. And unfortunately, again this will sound like the former news, the pre-hospital mortality was quite high in young women and has declined less in young women, compared to men.
So, the Erik study highlights the disparity for young women compared to young men. And then we have to recognize that most young patients in my hospitalization attributed to young patients is increasing. So this is probably a population that we need to be aware of. Regarding the older patients, there is a publication from the Opach Study looking at the sedentary behavior and cardiovascular disease in older women. And they looked at more than 5500 patients aged between 63 and all the way up until 97. And they looked at sedentary time and they looked at the duration of sedentary time all the way over eleven hours in some of the patients. And of course the higher the sedentary time was, the worse the cardiovascular disease risk was amongst the older women. So now we are recognizing that among older women, the post-menopausal or elderly women, the risk of cardiovascular disease rises with sedentary lifestyle.
And I think these three papers highlight the overall trend that we tend to see, maybe, better emphasis for comorbidity control. But at the same time we are now starting to recognize that in younger patients, especially in younger women the risk of MI is on the rise. And in older women, activity and remaining active and not having too much sedentary time are important to prevent cardiovascular disease.
Dr Carolyn Lam: Oh, Biykem, thank you for framing that so beautifully. So some good news, some bad news, and certainly some things we should be looking out for. You know, in another patient group that we always need to touch on when we talk about the Go Red for Women issue is pregnant women, or post-pregnancy. Could you comment, perhaps, on the systematic review that we have?
Dr Biykem Bozkurt: This is a very comprehensive, systematic review looking at the cardiovascular disease morbidity and mortality in women with a history of pregnancy complications. And they provide detailed systematic review and method analysis. It's becoming more apparent that the spectrum of cardiovascular disease ranges all the way from preeclampsia to arrythmia to pericardial myopathy. And we're recognizing this continuum both in the peripartum period, at the same time as the future risk. So those with preeclampsia and premature birth and delivery are associated with lifetime risk of cardiovascular disease. So, I think this paper is providing the right overview and a very comprehensive meta-analysis recognizing that pregnancy led to complications and morbidity and mortality in women.
Dr Carolyn Lam: Indeed. And it does just add so nicely to this issue, you know? Letting us know that we should watch out for the young women. We should watch out for the sedentary older women. And we should watch out for women with a history of pregnancy complications. But let’s switch tracks now. Sana, there was an amazing autopsy paper, actually, relating to sudden death in women. And as well as another original paper focusing on out of hospital cardiac arrest that is really very interesting. Would you like to tell us about those two?
Dr Sana Al-Khatib: Oh absolutely. I would love to. As someone who has devoted her life to the study of sudden cardiac death and you know, identifying factors, prevention. I really like that the paper looking at the risk of cardiac death in women and men. This study, Carolyn, was conducting in Finland, and the aim of the study was to determine autopsy findings and causes of death among women in a large population of sudden cardiac death.
They also were able to classify some EKG characteristics in men and women cardiac death victims. That really added helpful information. To do that, they systematically collected clinical and autopsy data from sudden cardiac death victims in Northern Finland between 1998 and 2017. So they actually had data on close to 5870 SCD victims. The findings were very interesting because they found that victims were significantly older than that. You know, so when they provided the median age it was 70 years for women versus 63 for men. So that was a significant difference there. And when they looked at the most frequently identified cause of death, they found that it was ischemic heart disease in both factions. Seventy two percent in women verses seventy six percent among men. And what was really striking about this was that the seventy two percent presence among women was higher than what had been reported in other theories.
They also reported that women were more likely to have lung ischemic cause of sudden cardiac death than men. It commented on the fact that primary myocardiac fibrosis was more likely to be found in woman victims rather than in men. And then they were able to identify some EKG factors stating that, in general, women were more likely to have a prior normal EKG than men. But that it increased the marker for sudden cardiac death with the presence of MDH with the polarization changes that were more commonly seen in women.
So, I thought that the findings were really interesting. They sure to be advance the field.
Dr Carolyn Lam: I couldn't agree more. Sex differences in sudden cardiac death. I don't think many people could tell you they knew much about it at all before this paper. And what about at a hospital cardiac arrest?
Dr Sana Al-Khatib: So, the other paper, which was really interesting, was a study that really looked at the public perception on why women receive less bystander CPR than men in out of hospital cardiac arrest. And this was an observation that was made a long time ago, Carolyn. So what's interesting for these investigators to be able to shed some light on this observation. What they did was they conducted a national survey of members of the public. And they were able to get 548 people to respond. Not a very high response rate, but pretty good for getting qualitative research studies. About fifty percent of the responders were women, so it was important to note that. And there was a good geographic distribution of the people; this was done in the U.S. And after they corrected their data, and they analyzed their data, the major thing emerged in terms of why the public perceived that women received less bystander CPR. The findings were really interesting.
The first finding was that people were concerned about being accused of sexual assault if they were to do CPR on the woman, which was interesting. Some actually were concerned that women were too weak or too frail. If they were to ever do CPR, might they cause any bone fractures, any injuries to the woman because they're more fragile, so to speak, than men. And their last theme was misperceptions about women in medical distress. What that meant was they felt that, well, you know, are women actually victims of sudden cardiac death? Yes, definitely, women can have sudden cardiac arrest and some people said, "Well, sometimes women can be overly dramatic and so maybe those presentations were not real presentations of sudden cardiac arrest," which I thought was really interesting.
I felt these were really interesting insights into why women don't receive CPR as much as men, and hopefully future interventions can be targeting these misconceptions or these concerns that the public has about doing CPR on women.
Dr Carolyn Lam: Isn't that so intriguing. The misconception that women are either too shy, too frail, or too dramatic. Oh my goodness. Anyway, that was all the original papers, which were fantastic. But I have to admit that one of the things that I love most about the Go Red for Women issues is that it talks about women in cardiology. And Biykem, you've always been such a huge mentor to me. And what I love about this issue is that there are a few papers, aren't there, that actually focus on the importance of this mentorship. Could you tell us about that?
Dr Biykem Bozkurt: It's a very important concept that I think is underlying a few papers in our issue. The first one is women in cardiology and perhaps the lack of increase in the representation of women in cardiology. Even though women make up about half of our medical graduates, among practicing cardiologists women comprise less than about twelve to fifteen percent of the population. That perhaps disparity hasn't changed in the last two decades. We tend to sometimes compare our profession to the surgical field, and I think gender inequality appears to be a little bit similar to general surgery and orthopedic.
But the paper by Ziman underlines the following: Even though our gender inequality is similar to the surgical field, to look at the temporal trends there has been a significant rise in female representation in general surgery. And actually, among medical trainees, about one third of the medical trainees, not fifty percent like us, one third of the medical trainees are in surgical fields after they go to medical school. But the female representation has been steadily increasing in the surgical fields; about three-fold out of cardiology. Whereas female representation cardiology has the main slot, so the surgical fields are doing a better job in either welcoming, supporting, and mentoring their female trainees than the cardiology field.
This is an important concept for us to recognize, and usually the disparity reasons are perceived to be gender and lifestyle and/or personal preferences. That doesn't appear to be the case. Perhaps the better role models and better mentorship could eliminate this disparity and this is underlined in the Olmein Mein paper by Ziman.
Another paper by Sharon Hunt also underlines this concept. She portrays the woman needed in cardiac transplantation from a historical and personal perspective, and underlines the following: We tend to have a large number of woman leaders in advance heart failure and cardiac transplantation. And part of this may be attributed to the fact that women have been part of the fabric, part of the readership, part of the group that has developed the field and has been practicing. And thus, there has not been a nation or incorporation of the women in the field. And thus, since they've been involved in the practice from the beginning, they have been seen as a natural partner. Even though cardiac transplantation is quite demanding, requires bedside presence, and hours which are usually used as a reason for women not to go into certain fields, such as interventional. In transplant, we don't seem to have that much disparity for women. Women tend to select this field on one of the reasons in Sharon Hunt's piece is identified as being part of the team from the beginning, and having good role models and mentors.
And finally, there is a research letter that identifies if the corresponding author is a female author. There is a large representation of co-authors. This is a very interesting finding by Ouyang stating that even though the female to male senior authorship rates have not been different over the years, if the senior author or the corresponding author is a female there tends to be a higher number of co-authors. This may suggest that female corresponding authors are able to mentor or include their partners or team members. Or vice versa, female co-authors may feel more invited and incorporated as a team. So, this paper also underlines that women in leadership positions connected to cardiology may serve as positive role models to recruit and retain talented junior female investigators.
Dr Carolyn Lam: Ah, indeed, indeed, indeed. So many topics that come close to my own heart. But Sana, among the numerous other papers here, we have two state of the art papers, two in-depth reviews, there are three frame of reference papers. Which one, or ones, stood out to you?
Dr San Al-Khatib: One important paper, Carolyn, you certainly mentioned is an online paper that was titled "Why are Young Black Women as High Risk for Cardiovascular Disease". I personally like this paper a lot because it highlights such an important issue that has great impact on public health. And sometimes the population of young black women may go unrecognized in terms of their risk of cardiovascular disease and what have you. So really the On My Mind paper tackles what are these things that are driving the worsening cardiovascular disease trends in this patient population. And what can we do about it? And they talk about how the awareness of heart disease and the leading cause of death among these women is actually more among black patients. And so, they talk about the need to really implement multi-level strategies to try to address this, raise awareness, identify disparities in care. They even also call for really investing in black women scientists.
And so, this was such a really good paper and I'm sure that the readers will enjoy it as much as I have.
Dr Carolyn Lam: Oh, thank you so much for that, Sana. That really, really makes for such a rich issue with such a lot of different papers. We're running out of time, so we don't even have the opportunity to really discuss, but I want to mention these so that the listeners will look out for them. Beyond the papers we've already discussed, we have state-of-the-art papers on cardiovascular care in women veterans and the management of cardiovascular disease in women with breast cancer. We even have two in-depth reviews. One on sex differences in advance heart failure therapies and a second on the role of breast arterial calcification in cardiovascular risk stratification in women. And finally, there's a research letter on the size of thoracic aortic aneurysms in women. So many papers, such a beautiful, beautiful issue. I just want to thank you both Sana and Biykem for leading this beautiful Go Red for Women issue.
Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
This program is copyright American Heart Association 2019.
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.
Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Is income volatility a new cardiovascular risk factor? You have to stay tuned to hear all about that. But for now, join Greg and I over a nice little coffee chat, because we're picking up the journal right here and I'm going to tell you about our two top picks this week. Greg, you go.
Dr Greg Hundley: Well my top picks, Carolyn, is really pertaining to senescence and senescent cardiomyocytes. Remember that? Senescence is a situation where there's a mismatch between energy demand and supply and so that facilitates the cells transitioning toward failure. They lose their ability to function. In other parts of the body, they lose their ability to divide.
And these investigators assessed altered calcium transfer from sarcoplasmic reticulum to the mitochondria, because that's being casually linked to the pathophysiology of aging in heart failure. Because the advanced glycation end products or AGEs accumulate through life, the authors thought that maybe this intracellular glycation would be occurring in aged cardiomyocytes and their impact on the sarcoplasmic reticulum and mitochondria. So, their study, they investigated both mice and humans and the found that ryanodine receptor glycation was associated with more pronounced calcium leak in mice and also interfibrillar mitochondria directly exposed to sarcoplasmic calcium release from aging mice had increased calcium content, compared to those with younger ones.
Now we're starting to implicate a mechanism by where senescence could be important in these mice. But of course, in Circulation in these wonderful basic science papers that we have, they also cover a translational human component. And what these group found is that there were higher levels of advanced glycation end products and reduced glyoxalase 1 activity present in left atrial appendages, from those patients that underwent surgery greater than 75-years-of-age, compared to individuals that were younger. And also, elderly patients exhibited hyper glycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity due to less respiring mitochondria.
Dr Carolyn Lam: Wow Greg, that was a huge summary and how nice to link aging or senescence with AGE or advanced glycation end products. Seriously, that was new to me. Okay look, bring it home. What are the clinical implications?
Dr Greg Hundley: What these investigators have done is now identified a previously unknown pathophysiological mechanism that may facilitate the transition from healthy, towards failing cardiomyocytes and the implication is that if you could disrupt that process, maybe you could halt the aging of cardiomyocytes. You got to be careful though I think with senescence, just as we know from the general literature. Senescence is a defense mechanism in cancer therapy, but it's a protagonist if you will, in aging. More to come in this field, but very exciting research.
So Carolyn, tell me about your first paper.
Dr Carolyn Lam: Happily, Greg. I'm going to take us to the cath lab and talk about functional assessment of epicardial coronary artery disease. This paper from Dr Koo and colleagues of Seoul National University Hospital, is the first to validate the physiological relevance and prognostic implication of all available novel resting pressure derived indices of coronary stenosis. This includes indices like resting full cycle ratio or RFR and diastolic pressure ratio or DPR, and they compared this to instantaneous wave free ratio or IFR and fractional flow ratio or FFR.
What they looked at was more than a thousand vessels in 435 patients and showed that all the resting ... Just the resting. Not hyperemic but resting pressure divide indices, closely correlated with each other and showed excellent agreement and the same discriminatory ability for no FFR. All the indices also showed a similar pattern of changes to different anatomical and hemodynamic stenosis severity, regardless of the target vessels and importantly showed similar diagnostic performance for myocardial ischemia, defined by gold standard PET derived CFR and hyperemic myocardial blood flow.
And finally, they showed that all these indices showed significant association with the two year vessel oriented composite clinical outcomes.
Dr Greg Hundley: So, do we still need to do adenosine infusions in the cath lab?
Dr Carolyn Lam: That's exactly what they're trying to drive at, because the major advantage of these resting indices, for example RFR over IFR, is that IFR doesn't require identification of a specific landmark or a specific time point during diastole. They may be simpler to perform and this first study showing their physiologic relevance and prognostic implication may enhance adoption of invasive physiologic assessment in daily clinical practice, which we know is important and a clinical benefit.
Dr Greg Hundley: Excellent. I tell you, it would sure save time if we could use indices like that.
Let me tell you about my next paper. This is from Renato Lopes, from Duke University Medical Center, in Durham. Also, one of your affiliates. In all of our cardiovascular/metabolic clinical trials today, cardiovascular death is a very important outcome. But what happens when, in doing a study like that and you have an undetermined cause of death, the US Food & Drug Administration Guidance indicates that deaths due to undetermined causes should be rare in well-run clinical trials.
And so what this group did is they looked at 127,049 enrolled participants from nine trials and they looked at how deaths were adjudicated. And across nine clinical cardiovascular trials, in different therapeutic areas, the proportions of deaths adjudicated as related to undetermined cause ranged from 7-to-22% and overall, had an average of 16%. Interestingly, in multi-variable analysis, death due to undetermined cause, was associated with the therapeutic area and the year of publication of the study, and then also several patient factors including: gender, age, the region of enrollment, and time from enrollment to death.
Dr Carolyn Lam: Gosh, this is so enlightening. Greg, having been on CECs and struggle with the adjudication, I really like this paper as well. But please, tell us all, why should we be concerned about this?
Dr Greg Hundley: Great question, Carolyn. First we might think about, if you're reading a study, the proportion of deaths due to undetermined cause should really fall within this range. And have a mean of maybe 16%. Second, what if there are higher rates due to undetermined cause? Well, that may indicate there are issues with the trial quality. And then finally, researchers, whenever they're doing a study, should really report on the proportion of deaths where cause was unable to be determined.
And there was a great editorialist, David Morrow, from Brigham and Women's Hospital, and really pointed out, you've got a couple factors here that lead to why there's undetermined cause of death. Maybe the documents are missing, or you're in a clinical situation where a subject lives alone, found dead, there's no autopsy. Uncertain duration. Sometimes there are limits on the study personnel; their ability to actually go out and acquire the data so that the team, like what you're on, can actually adjudicate the information. And a point that's made is really ... He used the word, doggedness, but with which he consistently worked toward and tried to get those medical records and pursue them, because that is very important.
When we think, well what's the importance of a study like this? It's valuable to those that perform studies, because as we're working with our study coordinators, we need to make that information known to them. If we don't collect the exact cause of death in these important cardiovascular interventional studies, we may end up with an improper result. And also, for the investigative team. A really important study I think, providing guidance for the first time now about what we should expect in undetermined cause of death, when we're looking at cardiovascular trials.
Dr Carolyn Lam: Indeed, and from talking about doing the trials to talking about a very important trial, I want to take you to The Partner 2 Trials and talk about the cost-effectiveness of Transcatheter Aortic Valve Replacement, or TAVR, compared to surgical aortic valve replacement, in patients at intermediate surgical risk.
Now we already know that TAVR is cost-effective, although not cost-saving. But cost-effective compared to surgical aortic valve replacement in those at high surgical risk. But this paper refers to intermediate surgical risk. And the analysis is from Dr Cohen and colleagues from Saint Luke's Mid-America Heart Institute, and it's an analysis of the Partner 2A Randomized Trial and the SAPIEN 3 Intermediate Risk Registry.
In summary, they found that TAVR was projected to lower total costs by $8,000.00 to $10,000.00. And to increase quality adjusted survival by 0.15 to 0.27 years, compared to surgical aortic valve replacement over a lifetime horizon.
Dr Greg Hundley: Wow! Carolyn, I've got two questions for you. First of all, how does TAVR save those costs? And number two, was this true for everyone? Were there any caveats or special subgroups that this was really applied to?
Dr Carolyn Lam: The cost savings in a TAVR cohort looked like they were driven by both a shorter length of stay during the index hospitalization, as well, as less resource utilization during follow-up. And that would be in the form of fewer hospital days, as well as fewer rehabilitation and skilled nursing facility days.
As for the caveats, you see that the authors did acknowledge that the long-term durability of the valves involved like the SAPIEN XT and the SAPIEN 3 valves is still unknown, and so lifetime costs associated with TAVR, may be higher than we assumed, owing to the need of more frequent repeat valve procedures for example.
Now if though, the long-term data demonstrate comparable late mortality with TAVR, and the surgical aortic valve replacement, these findings are really significant, because they suggest that TAVR may become the preferred treatment strategy for patient populations. Not only based on clinical outcomes, but even based on economic considerations.
Dr Greg Hundley: It looks like that long-term information is going to be really critical here, so we'll look for more in this area.
Dr Carolyn Lam: For sure. Wish we could keep chatting, but I think we need to move to the featured discussion.
Dr Greg Hundley: And now to the very fun segment of our discussion this week at Circulation on the Run. This is Greg Hundley, from VCU Health. Director of The Pauley Heart Center. And today we have a fantastic paper from Adina Zeki Al Hazzouri from Miami, transitioning to Columbia University. And also, our Associate Editor, Dharam Kumbhani from the University of Texas, Southwestern.
Today's paper, Adina is going to discuss is, Associations of Income Volatility with Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort. And what she's done is worked with the Coronary Artery Risk Development in Young Adult Study, we also know that as, CARDIA. And it's really a prospective cohort conducted in urban centers, in Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California. The goal here was to asses a block of individuals, younger, aged 23-35 years, identified in the time window of 1990-to-2005 and then followed subsequently to look at income volatility.
Adina, we're so excited to have you here. And can you tell us a little bit more about your study.
Dr Adina Zeki Al Hazzouri: Sure, the motivation for the study is the fact that we know that income volatility is on the rise. And what I mean by, income volatility, is the sudden and unpredictable change in income. And in the health researcher, we actually do not know as much, what is the effect or the influence of income volatility on health outcomes, and it is really common, most of us do experience these sudden or unpredictable changes in income. Whether they're little dips or little jumps in income. So they are really common, and I think it's really important to try to understand what would be their effect on health outcomes.
We were really interested in specifically understanding their effect on all-cause mortality and incidents of cardiovascular disease events, so we took advantage of an ongoing perspective cohort study. The cardio study that you just mentioned. And what is really nice about this study is they were really relatively young back in 1990 when we first had the measure of income. They were between ages 23-and-35. And they were followed for over 20-years, so we had repeatedly over 10-years, or 15-years, repeated measures of income. And then we were able then to look in the subsequent 10-years for incident events, cardiovascular events and all-cause mortality, and what is also interesting in this study is that these individuals, given that their age range, so that they are in the peak of their working years, which makes it even more interesting in terms of applicability and inference of those findings that we're making in this study.
We looked at, as I said, income volatility and we defined it basically as what is the standard deviation of these percent changes in income that you experience between the different visits in the study, which were on average, five years apart. And once we defined that, then we looked at it with outcome and what we really found was that those who experienced high volatility had around a two-fold increased risk of cardiovascular disease, as well as all-cause mortality.
We also looked at another measure of income volatility which is the number of income drops, so how many times you've dropped significantly, which we defined as a drop of more than 25%. And that is lower than your average income throughout the study period. And we found similar results.
Dr Greg Hundley: Adina, what could be the cause of this? What do you think as an investigative group, is the mechanism behind this finding?
Dr Adina Zeki Al Hazzouri: There could be various mechanisms playing roles here. Stress is obviously one of the important mechanisms. If you think about the instability of income, that instability in income could result in daily stresses, maybe inability to pay for bills. Also, that resulting in inflammation in all the stress pathway.
Also, you could think potentially having this instability could also maybe hinder access to care, maybe coping mechanisms related to stress could alter adherence to treatment. Whether maybe someone has to take daily medications, having those dips or changes, sudden changes in income, could alter your adherence to those medications and then subsequently influence your risk for cardiovascular disease.
Also, you could think access to health insurance. The social support, though it's not very well evidenced, but maybe if you've had always stable income, or low income, you're more likely to have more resilience. However, when you have these unpredictable changes, or sudden changes in income, you may not have that coping mechanism or support ready for you to deal with those sudden changes.
These are some of the pathways that we think of that could potentially be playing a key role here.
Dr Greg Hundley: Very good. Now let's turn to Dharam, our Associate Editor, from University Texas, Southwestern. Dharam, boy, surprising findings. A young cohort. I mean, they were 23-to-35 and in the next 10-years of their life they start to experience hard cardiovascular events. I mean, fatal and non-fatal myocardial infarction, and also, all-cause mortality. How do you put this in perspective, related to the workforce, and what do you think this means for this young population moving forward?
Dr Dharam Kumbhani: At the outset we obviously want to congratulate Adina and her group, for this really, very interesting study in cardiovascular EPY and broadly intersects in health economics and health policy, as well for obvious reasons.
Very interesting construct as you pointed out and what does this mean for younger subjects who experience these income volatility very early in their life. I think, just like any other EPY study, I think the perspective is helpful, because although the hazard ratio for these income volatility is two or higher, the absolute incidents rates are, again putting that in perspective is important, and so the absolute incident rates for example is somewhere between two-to-five, per 1,000 persons. So overall that impact, that's just helpful to understand what effects this would have.
Hopefully, that helps. But obviously, very interesting analysis and brings up a lot of questions. I think one thing I may add to what was just mentioned is ... And this was highlighted very nicely by the editorialist, Dr Spatz, and her colleague from Yale. About how this is globally in the financial toxicity space, and there are a number of these indicators that are now being carefully studied like in this study, such as wealth shock and as I said, financial toxicity. And how they actually have an impact on cardiovascular outcomes.
One of the feelings when you read a paper like this or when you read studies like this, and in fact this was one of our initial concerns as well, is to what extent you may have a component, or significant component of reverse causality. Your, "Patients who are sicker in some way," or have those culpabilities, be the ones that have these events is their relationship with other socio-economic indicators such as employment and how that would affect income volatility as well.
I think the authors have done a really terrific job responding to that. And again, it shows an association obviously we know that, that doesn't imply that it's cause[owed], but it's a very interesting association. And that it's helpful to speculate both on the mechanisms, which were just outlined, and also what this means from a health policy standpoint. What that would mean for researchers in the cardiology community, or policy makers, things like that. So I think this is a very nice analysis and definitely brings up a lot of discussion points.
Dr Greg Hundley: And a very important paper on multiple fronts. One, we've identified an issue in young, healthy individuals that could significantly contribute to adverse cardiovascular events. And then number two, I really liked your point on how this could impact public health policy, and maybe even how we need to think about reducing stress and how we design aspects of the workforce moving forward, so individuals don't suffer from these conditions.
I want to thank, Adina Zeki Al Hazzouri, from Columbia. And our Associate Editor, Dharam Kumbhani, for these excellent comments. We look forward to seeing you next week.
Dr Carolyn Lam: This program is copyright, American Heart Association, 2019.
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, from National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia.
Dr Carolyn Lam: What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking.
Dr Greg Hundley: Absolutely, and Myra, you're just going to love listening to her.
Dr Carolyn Lam: Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg.
Dr Greg Hundley: Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.
What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio.
Dr Carolyn Lam: But were there particular combinations within these groups that had particularly high bleeding risk?
Dr Greg Hundley: Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy.
Dr Carolyn Lam: Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.
All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.
Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk.
Dr Greg Hundley: So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically?
Dr Carolyn Lam: So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?
So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun.
Dr Greg Hundley: This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.
And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration.
Dr Carolyn Lam: Okay, but were there any complications?
Dr Greg Hundley: Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.
Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy.
Dr Carolyn Lam: I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.
The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure.
Dr Greg Hundley: So, what's the take-home message here?
Dr Carolyn Lam: This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients.
Dr Greg Hundley: Very good, Carolyn.
Dr Carolyn Lam: I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please.
Dr Myra Lipes: Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.
So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.
We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.
These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.
We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.
So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.
But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.
Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.
Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes.
Dr Greg Hundley: Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature?
Naveed Sattar: I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.
But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.
And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.
And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well.
Dr Myra Lipes: So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.
I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.
So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this.
Dr Carolyn Lam: Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.
Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.
This program is copyright American Heart Association 2019.