Podcasts about noacs

Play Episode Listen Later Jan 23, 2023 29:55

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway. Dr. Carolyn Lam: Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question. Dr. Peder Myhre: That is so interesting, Carolyn. I can't wait to hear this discussion. Dr. Carolyn Lam: Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis. Dr. Peder Myhre: Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn. Dr. Carolyn Lam: Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157. How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis. Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed. Dr. Peder Myhre: Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP. Dr. Carolyn Lam: Cool. That's interesting. So how did they do this, and what did they find? Dr. Peder Myhre: So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm. And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies. Dr. Carolyn Lam: Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction. Dr. Peder Myhre: Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain. Dr. Carolyn Lam: I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study. This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload. So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh? Dr. Peder Myhre: Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury. Dr. Carolyn Lam: Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find? Dr. Peder Myhre: Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study. Dr. Carolyn Lam: Indeed. Dr. Peder Myhre: And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury. Dr. Carolyn Lam: Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature. Dr. Peder Myhre: And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles." And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we? Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Subodh Verma: First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes. Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described. Dr. Greg Hundley: Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population? Dr. Subodh Verma: So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity. Dr. Greg Hundley: And how many subjects did you randomize? Dr. Subodh Verma: So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups. Dr. Greg Hundley: Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results? Dr. Subodh Verma: So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%. Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant. Dr. Greg Hundley: And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age? Dr. Subodh Verma: Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se. Dr. Greg Hundley: Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes? Dr. Christopher Granger: Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes. But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure. And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research? Dr. Subodh Verma: Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working. And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further. So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards. Dr. Greg Hundley: Very nice. And Chris, do you have anything to add? Dr. Christopher Granger: Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months. Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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.

Stroke Alert October 2022

Stroke Alert

Play Episode Listen Later Oct 20, 2022 41:00

On Episode 21 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2022 issue of Stroke: “Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk” and “Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage.” She also interviews Dr. Shadi Yaghi about his article “Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis.” Dr. Negar Asdaghi: Let's start with some questions. 1) Do hormone replacement therapies or oral contraceptives increase the risk of stroke? And if yes, does the age of the individual or the duration of therapy modify this risk? 2) Should survivors of intracranial hemorrhage who have atrial fibrillation be treated with antithrombotic therapies for secondary prevention of stroke? 3) And finally, what is the anticoagulant of choice for treatment of cerebral venous sinus thrombosis? We have the answers and much more in today's podcast as we continue to bring you the latest in cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. Welcome back to another amazing issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The October issue of Stroke covers a number of timely topics. As part of our October Literature Synopsis, we have a nice paper by Dr. Farida Sohrabji and colleague, which summarizes three recently published animal studies to evaluate the association between small vessel ischemic injury and either development of Parkinsonism or the future risk of Parkinson's disease. These studies looked at how ischemia, specifically involving the lenticulostriate arteries, can modulate the nigrostriatal dopaminergic pathway and ultimately lead to Parkinsonism. As part of our Original Contributions, we have the results of a small randomized trial out of Korea, which was led by Dr. Yun-Hee Kim from Sungkyunkwan University School of Medicine in Seoul, where we learned that doing 20 sessions of transcranial direct current stimulation for about 30 minutes for each session at home can improve post-stroke cognition. This was found to be specifically effective in patients with post-stroke moderate cognitive decline. Now, transcranial current stimulation can be given using a handheld device at home, and if truly proven safe and efficacious in larger studies, can dramatically change the landscape of stroke recovery in cognitive rehabilitation. I encourage you to review these articles in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Shadi Yaghi from Brown University. Shadi will walk us through a systematic review and meta-analysis of published studies to compare the safety and efficacy of direct oral anticoagulants to that of vitamin K antagonists in patients with cerebral venous sinus thrombosis. Our devoted Stroke Alert Podcast listeners recall that we did cover this topic in our March podcast when we reviewed the results of ACTION-CVT, a multicenter international study that was led by none other than Shadi himself. I'm delighted to have him as a guest on my podcast today to talk more about the seminal study and all things cerebral venous sinus thrombosis. But first, with these two articles. Millions of women worldwide use exogenous hormones, most commonly in the form of oral contraceptives and hormone replacement therapies. Despite the many different formulations of these drugs that are now available on the market, the two therapies are similar in that both combined oral contraceptives and hormone replacement therapies, or HRTs, contain various dosage of estrogen and progestin. Now, the principal difference between them being that the hormone contents of oral contraceptives are at high enough dosage to prevent ovulation, whereas hormone replacement therapies are considered more physiological as their aim is to return post-menopausal hormone levels to what they were before menopause. Well, by now, you must wonder how is any of this even relevant to vascular neurology? Well, the answer lies in the close relationship between hormonal therapies and stroke. But before we get to that, we have to review a few things. First of all, it's long been known that the endogenous estrogen has strong and protective effects on the arteries. It promotes vasodilation and cell survival of the endothelial layer. It increases the endothelial mitochondrial efficiency and stimulates angiogenesis. In other words, endogenous estrogen is good for vascular health. And in fact, that's why we think that premenopausal women, in general, are at a lower risk of stroke as compared to their age and vascular risk factors–matched male counterparts. And to make things even better for estrogen, there's enough evidence to suggest that exogenous estrogen also does all of these good things for the endothelium. So, why are we even talking about an increased risk of stroke associated with use of hormonal therapies? The problem is, we have to remember that exogenous estrogen also does other things. It can increase the blood concentration of procoagulants, which, in turn, can increase the risk of thromboembolism, especially venous thrombosis. But there's still a lot of unknown on this topic. For instance, the majority of the prior research on the topic involves postmenopausal women using hormonal therapies. Some of that research has actually suggested that HRTs may be protective against vascular events, while others showed the opposite. Well, we know that a majority of oral contraceptive users are actually much younger and use these medications premenopausal. So, there seems to be a lot of gaps in our current knowledge on the simple question of whether or not oral contraceptives and hormonal replacement therapies do, in fact, increase the risk of stroke or not. In the current issue of the journal, a group of researchers led by Drs. Therese Johansson, Torgny Karlsson, and Åsa Johansson from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden set out to fill some of these gaps with their study titled, "Oral Contraceptives, Hormone Replacement Therapy, and Risk of Stroke," as part of a large UK Biobank population-based cohort. Just a bit about the UK Biobank. This was a large population-based cohort from 2006 to 2010 that included over 500,000 residents of the United Kingdom between the ages of 37 and 73. Participants at the time of enrollment would have extensive information collected from them through questionnaires, interviews, health records, physical measures, as well as some imaging and biological samples. Data on each participant was collected from the time of their birth all the way to the day of assessment, which is interesting, because the day of assessment would then count as the end of the follow-up for each participant. Now, for the current study, they included over 250,000 women of White race in whom information required for the study on whether or not they use hormonal therapies, duration of treatment, age at the time of exposure was available. And just a quick comment about their methodology. They analyzed their cohort once for oral contraceptive use and once for HRT use and compared each group to a reference group of either women who never used their set therapy or the number of years they contributed to the study prior to initiating that set treatment. So, for instance, if a person started using oral contraceptives at the age of 21, all of the years that she contributed to the study before that age would count as non-exposed user years and were included in the control cohort. So now, on to their findings. A total of 3007 stroke diagnosis of any type were identified prior to the initial visit to the assessment center, which, as we mentioned, was the end of the follow-up in the study. Of these, 578 were ischemic strokes, 177 intracerebral hemorrhage, and 478 were subarachnoid hemorrhages. But as expected for any large cohort, over half of total strokes were self-reported as stroke of any type and could not be classified into any of the above subtypes. Now, let's look at the effects of oral contraceptives on the outcome of stroke. Overall of the women included in the study, 81% were classified as oral contraceptive users, while 19% reported never having used oral contraceptives at any point during the study. On the association between oral contraceptive use and the risk of stroke, at first glance, things looked OK. The hazard rates of any stroke for any stroke subtypes were not different between women who had used oral contraceptives as compared to those in the reference group. That's great news. But when they looked deeper, they realized that the odds of development of any stroke was actually quite high during the first year after the initiation of oral contraceptives with hazard rate of 2.49 for any stroke, while there was no difference in hazard rates found during the remaining years of use and after discontinuation of oral contraceptive use. So, meaning that there was no lingering effects of oral contraceptives on increased risk of stroke after the first year or after discontinuing the medication. Now, on to HRTs. In total, 37% of women in the study had initiated HRTs at some point during the study, while 63% had never used this therapy. Here's the bad news. Overall, HRTs did increase the risk of stroke. An approximately 20% increase event rate of any stroke was noted among women who had initiated HRTs as compared to those who had not. When analyzing stroke subtypes, the use of HRTs was associated with increased risk of only the subarachnoid hemorrhage subtypes. We don't know why. Diving deeper, in considering timing of HRT initiation, very similar to what was observed for the oral contraceptives, during the first year after starting the HRTs, the treatment group was twice more likely to suffer from any type of stroke, and the hazard rate was also increased for all three stroke subtypes that were available in the study. But, unlike oral contraceptives, the hazard rate of any stroke remains significantly high even after the first year of use, not just for those who continued HRTs, but sadly, even for those who discontinued the therapy. Though the risk remained high, the hazard ratio declined over time as we went further away from the first year when treatment was initiated. So, bottom line, if women had initiated HRTs at some point in their life, the hazard risk of any stroke increased significantly in the first year. That hazard risk did decline over time, but it always remained significantly higher than non–HRT users. Now, what about timing of treatment in relation to the onset of menopause? Is the risk of stroke any different if women start on HRTs prior to or after their menopause? The answer is no. Initiation of HRTs was associated with an increased hazard rate of any stroke if it was started pre- or postmenopausal, but the risks were higher if the treatment was started prior to menopause. So, in summary, this large population-based cohort has truly given us some very important practical findings. We learned that both oral contraceptives and hormone replacement therapies do, in fact, increase the risk of stroke, an effect that was most notable in this study in the first year after initiation of both of these therapies, and in the case of oral contraceptives, was just actually limited to that one year alone. Why does this happen? I guess the easy answer is that these drugs, as we noted earlier, have an immediate prothrombotic effect, which gradually weakens over time. That's one plausible explanation, but for instance, why HRTs increase the risk of subarachnoid hemorrhage is something we can't explain based on the prothrombotic effects of HRTs. So, we have to come back to the vessels, the impact of hormone therapies and estrogen specifically on the blood vessels, on the endothelial cells, the potential increase in blood pressure, especially early on in the course of treatment with these medications. And also, we have to think about the role these drugs may play in increasing inflammatory markers, providing a more suitable milieu for accelerated atherosclerosis, as to why these associations were noted in this study. And it's fair to say that we need more research on this topic in the future. One challenging scenario that we commonly face in our daily practice is deciding whether or not we should resume antithrombotics in patients with atrial fibrillation who have survived an intracranial hemorrhage. The majority of intracranial hemorrhage survivors with atrial fibrillation actually have a very high CHA2DS2-VASc score, which means that they are actually at a very high risk of future ischemic stroke and systemic embolic events unless they're treated with anticoagulants. On the other hand, the risk of spontaneous intracranial bleeding is substantially higher in a person who has previously suffered from one, let alone if we treat them with anticoagulants. And to make matters worse, we have little evidence from the literature to guide us. So, in the current issue of the journal, in the study titled "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage," a group of researchers from the UK led by Dr. Deirdre Lane, Professor of Medicine at the University of Liverpool, performed a much needed systematic review and meta-analysis of the available evidence on this subject. I have to say that lately, it seems that we've been covering a few of these reviews in our podcasts, and we are just getting started. In fact, my next paper in today's episode is also a systematic review and meta-analysis. These papers are packed with details, a testament to the work needed to complete them, but I have to say that even summarizing these papers for a podcast has been a bit challenging. So, feel free to put me on pause, go get some coffee, and let's power through this one together. For their methods, they used the usual search engines looking for papers that included adults over the age of 18 with atrial fibrillation who had survived a non-traumatic spontaneous intracranial hemorrhage of any size, any type, and any location, be it lobar, brain stem, deep, cerebellar, subdural, epidural, or subarachnoid hemorrhage. And very importantly, they included even those with evidence of microbleeds on neuroimaging. The intervention of interest was either long-term oral anticoagulation or antiplatelet therapy versus no antithrombotic use for the following three outcomes of interest: number one, recurrent thromboembolic events; number two, recurrent intracranial hemorrhage; and number three, all-cause mortality. Just a quick note that for this analysis, they excluded studies that looked at either short-term anticoagulation or non-oral anticoagulation use for any reason that was given to the patient other than for secondary prevention of stroke. For example, if a patient suffered from a pulmonary embolism and was treated with IV heparin or, for a short period of time after that, with oral anticoagulation, those patients or those studies were excluded from this meta-analysis. So, with this criteria, they pulled over 4,000 citations and abstracts, and finally included 20 papers that were published between 2015 and 2021 for a total of over 50,000 participants for this meta-analysis, very nice sample size. Most of the papers included were observational cohorts, but in addition, we had two small randomized trials, and I want to take a moment and review these trials for our listeners. The first one was a small noninferiority pilot trial out of the UK, the SoSTART trial, that looked at any anticoagulant versus either antiplatelet therapy or no antithrombotics in this population, and the other trial was the Phase 2 trial, the APACHE-AF, that studied apixaban versus no anticoagulation after anticoagulant-associated intracerebral hemorrhage. A reminder that both of these trials were published in Lancet Neurology in 2021. And before we move on to the findings of the meta-analysis, it's worth noting that they had included a mix of patients, some were oral anticoagulant–naive, and some had developed their index intracranial hemorrhage while already on treatment with anticoagulants or antiplatelet therapies. OK, now on to their findings, as mentioned, we're going to review three outcomes of recurrent thromboembolism, recurrent intracranial hemorrhage, and all-cause death for the following three groups: group one, oral anticoagulant therapy versus no therapy; group two, oral anticoagulation therapy versus either antiplatelet treatment or no therapy; group three, comparing new oral anticoagulants versus warfarin. So, for the first outcome of recurrent thromboembolic events in group one, when comparing oral anticoagulant therapy to no therapy, the study showed a significant reduction in thromboembolic events in favor of oral anticoagulation compared to no therapy. That's great news. Next, analysis of the studies that compared oral anticoagulation versus either antiplatelets or no therapy didn't show the same difference in prevention of embolic events in favor of either groups. Actually, no difference was noted between the two groups. Number three, now, in terms of comparing NOACs to warfarin, three studies had the information on this comparison, and they reported a significant reduction in the risk of thromboembolic events with NOAC as compared to warfarin. So, great news for oral anticoagulation overall, and especially for NOACs. Now, on the next outcome. Our second outcome was a recurrent intracranial hemorrhage. Keeping in mind that they included some studies where the outcome was defined as any form of intracranial hemorrhage, meaning they included subdurals, epidurals, etc., and some studies only included the outcome of intracerebral hemorrhage. So, on to the first group, comparing oral anticoagulants to no therapy, the pooled estimate revealed no statistically significant difference between oral anticoagulant–treated patients to those who were not treated with any antithrombotics on the risk of recurrent intracranial hemorrhage. That's great news. Next, on our second group, for the same outcome of recurrent intracranial hemorrhage, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found that oral anticoagulation was associated with a higher risk of recurrent intracranial hemorrhage as compared to antiplatelets or no therapy. And finally, third group comparing new oral anticoagulants to warfarin for the same outcome, the risk of recurrent intracranial hemorrhage was significantly reduced in patients treated with NOACs as compared to warfarin. And now, we're finally on to our last outcome of the study, which is the outcome of all-cause mortality. So, again back to group one, comparing oral anticoagulants to no therapy, this meta-analysis showed a significant reduction in all-cause mortality rate associated with oral anticoagulation. That's, again, great news. Next group, for the same outcome of mortality, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found no significant difference in the mortality rates between the two groups. And finally, comparing NOACs to warfarin, the pooled estimate showed that NOACs were associated with a significantly reduced risk of all-cause mortality. Amazing news for NOACs. So, in summary, here's what we learned from this big study. Oral anticoagulation use after intracranial hemorrhage in patients with atrial fibrillation did significantly reduce the risk of thromboembolic events and all-cause mortality without significantly increasing the risk of recurrent intracranial hemorrhage. In general, new oral anticoagulants, or NOACs, are preferred to warfarin as they do prevent embolic events with a lower risk of recurrent intracranial hemorrhage. But, of course, we still have a lot more questions. For instance, would any of the outcomes mentioned above be different in patients with lobar intracerebral hemorrhage, a condition typically associated with amyloid angiopathy, which carries a high risk of development of intracerebral hemorrhage? Also, we have to keep in mind that the majority of the studies included in the meta-analysis were observational. So, there remains an urgent need for a larger randomized trial on this subject, and we have to stay tuned for more research. Cerebral venous sinus thrombosis, or CVST, is an uncommon form of stroke resulting in headaches, seizure, or focal neurological symptoms due to either intracranial hemorrhage or venous ischemic infarcts. The rarity of the disease has made it difficult to study as part of randomized trials, so current treatment guidelines for CVST are consensus-based with much of the recommendations extrapolated from data on treatment of patients with systemic deep vein thrombosis. In general, based on the current evidence, the field agrees that a patient with CVST should be anticoagulated. The decision that is difficult and sometimes inappropriately delayed in the setting of acute hemorrhage in the brain. And not surprisingly, there's significant equipoise around the choice of anticoagulant, duration of therapy, and the role of heroic therapies, especially in the acute setting. Currently, there are a number of ongoing trials to address some of these issues. The direct oral anticoagulants present an attractive alternative to vitamin K antagonists for treatment of patients with CVST. This is partly because of their convenience of use. But how do direct anticoagulants compare in safety and efficacy to the vitamin K antagonists in the setting of CVST is less known. In our March podcast, we reviewed the results of ACTION-CVT, which was a multicenter international study that compared the safety and efficacy profile of the direct oral anticoagulants to that of warfarin in routine practice. The study included over a thousand imaging-confirmed CVST patients from multiple centers in the US, Italy, Switzerland, and New Zealand. And if you missed it, no worries at all. We're here to review some of the results again, as in this issue of the journal, many of the ACTION-CVT investigators, led by Dr. Shadi Yaghi, present the results of a systematic review and meta-analysis comparing the safety and efficacy of DOACs, or direct oral anticoagulants, to that of vitamin K antagonists. I'm joined today by Dr. Yaghi himself to discuss ACTION-CVT and the current meta-analysis. Dr. Yaghi is a Director of Vascular Neurology at Lifespan and Co-Director of Comprehensive Stroke Center and a Director of Research at the Neurovascular Center at Rhode Island Hospital. Good afternoon, Shadi, and welcome to our podcast. Dr. Shadi Yaghi: Good afternoon, Dr. Asdaghi. Thank you so much for having me. Dr. Negar Asdaghi: Thank you. And please call me Negar. Congrats on the paper. Before we talk about the meta-analysis, can you please remind us of the results of ACTION-CVT and why the systematic review, in your opinion, was an important next step to that effort? Dr. Shadi Yaghi: Thank you so much for having me and for bringing up ACTION-CVT. So ACTION-CVT is a real-world multicenter international study that used real-world observational data to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The reason why we did ACTION-CVT was, as you know, cerebral venous thrombosis is a rare disease, and it's hard to have large studies that would be powered enough to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists. So, most of the studies that were done are small, retrospective. There's one randomized controlled trial, but most of them are underpowered to detect the difference between the two groups. So, we decided to do a large-scale international multicenter study using real-world data to compare the safety and efficacy of both. Dr. Negar Asdaghi: OK, so we're glad you did. Let's start with the methodology of the current meta-analysis. Can you please give us an overview of the inclusion criteria for selection of the papers and the intervention and outcomes that you were interested in? Dr. Shadi Yaghi: Of course. So, this is a systematic review and meta-analysis that included studies comparing direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The studies needed to have the two groups included, the direct oral anticoagulants and vitamin K antagonists, and they need to include at least one of the outcomes in our study to compare this outcome between the two groups. In addition, we included articles published in English, and we also included papers that had five patients or more in each group. Dr. Negar Asdaghi: Perfect. So just recap for our listeners, in order to have been included in the meta-analysis, the paper had to have a reasonable number of patients, and you put that reasonable at the number five, and also they had to have at least one of the outcomes of interest reported in their papers. And those outcomes were either recurrent venous thromboembolism or recanalization rates. Right? Dr. Shadi Yaghi: Correct. Yes. Dr. Negar Asdaghi: Perfect. So with that, how many papers did you have to go through to come up with the current number of papers included? Dr. Shadi Yaghi: That's a great question. We had a little over 10,000 papers, and then we went through a screening process. We used this tool that was developed by Brown University. It's called Abstrackr, and what you do is, we did the search and using several databases like PubMed, Cochrane, and then we included all these studies. We uploaded them in Abstrackr, and Abstrackr was utilized to be able to review all these abstracts and select studies that may or will probably qualify and then go through the studies and details that would qualify. So, we had about 10,000 studies with the initial search, and we had two reviewers go through each abstract, and from these 10,665, we excluded 10,411, and that left us with 254 studies. And then we went through these 254 studies in details. And then finally, we had 19 studies included that met our inclusion/exclusion criteria. And these 19 studies included three randomized control trials and 16 observational studies. Dr. Negar Asdaghi: Incredible effort. So, three randomized trials in this meta-analysis and 16 observational studies. I think we're very ready to hear the primary outcomes. Dr. Shadi Yaghi: Yeah, so, the primary outcomes were recurrent venous thrombosis, and that included recurrent venous thromboembolism like peripheral DVTs or PEs, for example, and including recurrent cerebral venous thrombosis. And we know that most of the events are recurrent VTEs, not CVTs, like probably about two-thirds to three-quarters were VTEs, and a third to a quarter were CVT. And then the other efficacy outcome is venous recanalization on follow-up imaging. And we found that direct oral anticoagulants and warfarin were not significantly different in the primary efficacy outcomes. Dr. Negar Asdaghi: Thank you. I just want to repeat this for our listeners. So, you mentioned some important information here. First one was the fact that about three-quarters of recurrent events were actually systemic thromboembolic events rather than cerebral thromboembolism. So, an important outcome to keep in mind for our practicing physicians. And the fact that DOACs did the same as compared to vitamin K antagonist. So, I think you can already guess my next question, and that is, was there any compromise on the safety profile when using DOACs as compared to vitamin K antagonists in this meta-analysis? Dr. Shadi Yaghi: Thank you. That's a great question. In ACTION-CVT, we found that there was a lower risk of major hemorrhage with direct oral anticoagulants compared to vitamin K antagonists. In this systematic review and meta-analysis, we didn't find a significant difference, but there were fewer events in patients treated with direct oral anticoagulants versus vitamin K antagonists. This did not reach statistical significance, but if you look at the raw data, it's kind of along the same lines as ACTION-CVT, so the risk of major hemorrhage was about 3.5% with warfarin, and that was about 2% with direct oral anticoagulants. Dr. Negar Asdaghi: So, again, very important finding, and I want to repeat this for our listeners. So, important finding number one was that there was a superiority in favor of DOACs that you found in terms of a reduced risk of intracerebral hemorrhage in ACTION-CVT. You didn't find this superiority in the meta-analysis, but there was sort of a hint to perhaps lower risk of intracerebral hemorrhage in patients that were treated with DOACs. Did I get that right? Dr. Shadi Yaghi: Yes, that is correct, and in addition, also major hemorrhage in general, and that included also ICH. Dr. Negar Asdaghi: Oh, OK, so not just intracranial, but systemic hemorrhages as well. All right. Very good. So, I think my next question would be, why do you think that DOACs have a lower chance of causing hemorrhage? Dr. Shadi Yaghi: Yeah, that's a really good question. This is not unexpected with DOACs as opposed to vitamin K antagonists. We saw these same trends in patients with atrial fibrillation. We saw improved bleeding profiles with direct oral anticoagulants as compared to vitamin K antagonists. And the risks were along the same lines that we found in patients with cerebral venous thrombosis in ACTION-CVT. Also in the VTE trials as well, there was also reduced bleeding complications with direct oral anticoagulants as compared to vitamin K antagonists. So, it was kind of reassuring to see the same results in patients with cerebral venous thrombosis. Dr. Negar Asdaghi: Perfect, so kind of expected based on what we know from treatment of systemic conditions with DOACs. The next question I have for you is that in routine practice, treatment of cerebral venous sinus thrombosis almost always starts parenterally with either unfractionated heparin or low molecular weight heparin and then we switch to an oral agent. In the observational studies, did you find any differences in terms of timing of this switch or characteristics of the patients in whom vitamin K antagonists were chosen over direct oral anticoagulants? Dr. Shadi Yaghi: Thank you very much. Most of the studies did not report these details. I think the one study, off the top of my head, that does report the differences in characteristics between the two groups is RESPECT-CVT. That's the randomized controlled trial comparing dabigatran to vitamin K antagonists. In this study, there was a treatment with parenteral anticoagulation for several days, I think seven to 14 days, prior to transitioning to oral anticoagulation. And this is generally my practice. I typically would treat patients with at least seven days or so parenteral anticoagulation, and once they're clinically stable, then I would transition them to oral anticoagulation, either vitamin K antagonists or direct oral anticoagulant. Dr. Negar Asdaghi: And I think my next question is along the lines of this question as well. We have several direct oral anticoagulants now available on the market. What was the most common DOACs used for treatment of CVST in these studies, and did you note a preference for the use of any particular agent over others? Dr. Shadi Yaghi: Thank you so much for the question. Anti-Xa inhibitors were much more common than dabigatran, and the anti-Xa inhibitors most commonly used were apixaban and rivaroxaban. It's in line with what we saw in ACTION-CVT as well, although most of the randomized controlled trials or the largest randomized controlled trial, RESPECT-CVT, used dabigatran, but overall people have been using anti-Xa inhibitors, more particularly apixaban, which was also in line with what we saw in ACTION-CVT. Dr. Negar Asdaghi: But I think it's fair to say that we don't really have data on superiority of one over others. Is that fair? Dr. Shadi Yaghi: Yes, that is correct. Dr. Negar Asdaghi: OK, and so now, where are we at in terms of the future of studies on this topic? We have one ongoing randomized trial now? Dr. Shadi Yaghi: Yes, we have one randomized controlled trial ongoing, and this is the SECRET trial, and it's looking at rivaroxaban versus vitamin K antagonists in patients with cerebral venous thrombosis. There's another study, it's a prospective observational study that's called the DOAC-CVT study. It's an international study also looking at real-world data prospectively to see if there's a difference in outcomes between the two groups. Dr. Negar Asdaghi: So, we look forward to the results of those studies. Shadi, a follow-up question I have on this topic is, how long should a duration of therapy be in idiopathic cases of cerebral venous sinus thrombosis? Dr. Shadi Yaghi: Thank you so much for this question. So, it's unknown at this point for how long should we treat. The key things from the treatment are first achieving venous recanalization, and second is preventing another venous thromboembolic event from happening. So, regarding the venous recanalization, studies have shown that there's not a lot of recanalization beyond four months of treatment. So, a lot of the recanalization really happens early, and continuing anticoagulation beyond the six-months interval, for example, in order to achieve further venous recanalization probably has limited utility. And the second important reason why we treat patients with anticoagulation is also to reduce the risk of a recurrent venous thromboembolic event or cerebral venous thrombosis. And for that, if it's a provoked CVT, then I think usually it's three to six months. If it's unprovoked, up to maybe six to 12 months or even longer, depending on the profile. And if there's a persistent provoking factor, such as cancer, antiphospholipid antibody syndrome, then the treatment is lifelong or until this condition subsides. There's a lot of controversy about the duration of treatment. The European guidelines were very helpful in identifying the duration of treatment. Hopefully, also, we have some guidelines or at least a scientific statement by the AHA that also doles details out and provides some guidance to practitioners. Dr. Negar Asdaghi: Shadi, what should be our top two takeaways from the current meta-analysis and also ACTION-CVT? Dr. Shadi Yaghi: So, really, the top two from ACTION-CVT and the meta-analysis are, first is direct oral anticoagulants have a comparable efficacy to vitamin K antagonists in terms of recurrent venous thrombosis and achieving venous recanalization on follow-up imaging. And then the second point is direct oral anticoagulants are probably safer than vitamin K antagonists. We have to keep in mind that this data is based mostly on observational studies. And, as we mentioned earlier, we need more randomized controlled trials to support these findings. Dr. Negar Asdaghi: Dr. Shadi Yaghi, it was a pleasure interviewing you on the podcast. Thank you very much for joining us, and we look forward to having you back on the podcast and reviewing this topic again in the future. Dr. Shadi Yaghi: Thank you so much. I appreciate you having me. Dr. Negar Asdaghi: Thank you. And this concludes our podcast for the October 2022 issue of Stroke Please be sure to check out this month's table of contents for the full list of publications, including an important update from the European Stroke Organisation by Prof. Martin Dichgans. I also want to draw your attention to this month's InterSECT paper, which is our International Stroke Early Career and Training section, to discuss the key topic of burnout and mental health amongst physicians, especially amongst neurologists and stroke neurologists. It's alarming to read in this article that neurology is one of the specialties with the highest reported rates of burnout syndrome, and stroke neurologists are at particularly higher risk than other neurological subspecialties. The article tackles some tough subjects, such as the barriers for physicians to seek help and important strategies to mitigate burnout and how to improve mental health in general. I think it's also timely to know that October is the Mental Health Awareness Month, and the theme for October 2022 is "Back to Basics." The basics of recognizing the burden of stress, anxiety, the burden of isolation and depression, not only on those who we take care of, but also on those who give care to us. So, whether you're a stroke physician, a stroke caregiver, or whether you've been touched by this disease in some way or shape, please know that you are part of the stroke community and a part of our Stroke podcast family. Thank you for listening to us, and, as always, stay alert with Stroke Alert. 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, visit AHAjournals.org.

Circulation October 18, 2022 Issue

Play Episode Listen Later Oct 17, 2022 22:48

This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?" Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first? Dr. Greg Hundley: You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations. Dr. Carolyn Lam: Wow. Sounds like a really large effort, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed. Dr. Carolyn Lam: Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial. Dr. Greg Hundley: The DELIVER trial. Carolyn, tell us about the DELIVER trial? Dr. Carolyn Lam: Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach. And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail. Dr. Greg Hundley: Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function. Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension. Dr. Carolyn Lam: Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find? Dr. Greg Hundley: Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension. Dr. Carolyn Lam: Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue? Dr. Greg Hundley: You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.” Dr. Carolyn Lam: There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg? Dr. Greg Hundley: You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Sunil Rao: Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk. Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications. Dr. Greg Hundley: Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects? Dr. Sunil Rao: Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge. Dr. Greg Hundley: Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population? Dr. Sunil Rao: We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation. Dr. Greg Hundley: Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results? Dr. Sunil Rao: Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms. Dr. Greg Hundley: And did you find the same results for the men and the women? And what about older individuals and younger individuals? Dr. Sunil Rao: Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study. Dr. Greg Hundley: Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies? Dr. Gregory Lip: Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants. And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding. Dr. Greg Hundley: Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research? Dr. Sunil Rao: I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding. Dr. Greg Hundley: And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further? Dr. Gregory Lip: Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants. Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance. Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection. 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. 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.

Circulation October 4, 2022 Issue

Play Episode Listen Later Oct 3, 2022 25:49

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study." Dr. Carolyn Lam: Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA? Dr. Greg Hundley: Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure. Dr. Carolyn Lam: Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology. However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes. Dr. Greg Hundley: Oh wow, Carolyn, this sounds really informative. So what did they find? Dr. Carolyn Lam: Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts. Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis. Dr. Greg Hundley: Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction. So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily. Dr. Carolyn Lam: All right. So the Paradise MI echo substudy, what did they find? Dr. Greg Hundley: Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial. Dr. Greg Hundley: Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us? Dr. Carolyn Lam: Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction. Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new. Dr. Carolyn Lam: Wow, that's interesting. So what did this paper find? Dr. Greg Hundley: Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting. Dr. Carolyn Lam: Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing. Dr. Greg Hundley: Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke? Dr. Carolyn Lam: Yep. In patients with EF, here we go. Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation. Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place? Dr. Signild Åsberg: Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question. Dr. Jonas Oldgren: My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies. So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?" And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment? Dr. Carolyn Lam: Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used? Dr. Jonas Oldgren: Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence. And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study. Dr. Carolyn Lam: Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results? Dr. Signild Åsberg: Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients. Dr. Carolyn Lam: That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome? Dr. Jonas Oldgren: Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well. So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started. So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention. Dr. Carolyn Lam: Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit? Dr. Signild Åsberg: We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase. Dr. Carolyn Lam: I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds? Dr. Signild Åsberg: We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale. Dr. Carolyn Lam: Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results. Dr. Signild Åsberg: Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that. We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation. Dr. Jonas Oldgren: And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials. So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences. And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients. Dr. Carolyn Lam: Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view? Dr. Signild Åsberg: Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention. Dr. Jonas Oldgren: I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study. Dr. Carolyn Lam: And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week. 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.

director university dna patients run sweden defining singapore richmond signal bethesda copyright chen lam ef american heart association associate editor lv circulation intensive care units pah uppsala university rne sglt2 noac mississippi medical center hfpef empagliflozin vcu health noacs duke national university nhlbi kaplan meier carolyn lam emperor preserved nih clinical center

The beginning of the end for NOACs? The extra mile

Play Episode Listen Later Sep 6, 2022 19:31

This podcast is a follow-up to Bayer's symposium at ESC 2022, ‘The beginning of the end for NOACs? The extra mile'. In this episode, Dr Manesh Patel and Professor Rupert Bauersachs expand on the discussions from the symposium, providing further insight into the management of frail patients with AF and VTE. The experts also provide their perspectives on the treatment of paediatric patients with VTE and patients with cancer-associated thrombosis, evaluating the available evidence to guide decision-making for these particularly vulnerable patients. The views and opinions expressed throughout this podcast are those of the speakers based on their expertise and do not necessarily reflect those of Bayer. Further details: • The EINSTEIN programme publications can be found here for EINSTEIN PE (https://www.nejm.org/doi/full/10.1056/NEJMoa1113572), EINSTEIN DVT (https://www.nejm.org/doi/full/10.1056/NEJMoa1007903), EINSTEIN Pooled (https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-11-21), EINSTEIN CHOICE (https://www.nejm.org/doi/full/10.1056/nejmoa1700518) and EINSTEIN JUNIOR (https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30219-4/fulltext) • Real-world evidence published by Craig Coleman on the efficacy and safety of rivaroxaban versus warfarin in frail patients with VTE can be accessed here: https://www.amjmed.com/article/S0002-9343(18)30202-X/fulltext • The XALIA study publication can be found here: https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(15)00257-4/fulltext • The findings from the XANTUS trial are available here: https://academic.oup.com/eurheartj/article/37/14/1145/2466063 • Access the ROCKET AF manuscript here: https://www.nejm.org/doi/full/10.1056/nejmoa1009638 • The elderly subgroup analysis of ROCKET AF can be found here: https://www.ahajournals.org/doi/10.1161/circulationaha.113.005008 • Findings from the SAFIR trial can be accessed here: https://heart.bmj.com/content/107/17/1376 • Find the edoxaban phase II trial paper here: https://www.thieme-connect.com/products/ejournals/abstract/10.1160/TH10-01-0066 • Read the SELECT-D study paper here: https://ascopubs.org/doi/10.1200/JCO.2018.78.8034 • Information on the OSCAR trials can be found here for the UK (https://clinicaltrials.gov/ct2/show/NCT05112666, https://abstracts.isth.org/abstract/comparison-of-effectiveness-and-safety-of-direct-oral-anticoagulant-versus-low-molecular-weight-heparin-treatment-for-venous-thromboembolism-in-patients-with-active-cancer-the-oscar-uk-study/) and the US (https://clinicaltrials.gov/ct2/show/NCT04979780, https://www.sciencedirect.com/science/article/pii/S0006497121040908) • Details on the Mayo Clinic prospective cohort study are available here: https://www.mayoclinicproceedings.org/article/S0025-6196(21)00435-3/fulltext • Support for the proportion of patients not receiving anticoagulation can be accessed here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278389/#CIT0011 • For anticoagulant dosing information, see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf) and warfarin (https://www.medicines.org.uk/emc/product/3064/smpc) Audio: MA-M_RIV-ALL-1236-1 Shownotes: MA-M_RIV-ALL-1237-1

uk real european albert einstein af esc gb mayo clinic bayer findings beginning of the end extra mile vte jco safir noacs craig coleman xantus

Stroke Alert August 2022

Stroke Alert

Play Episode Listen Later Aug 18, 2022 35:27

On Episode 19 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2022 issue of Stroke: “Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion” and “Recurrent Ischemic Stroke and Bleeding in Patients With AF Who Suffered an Acute Stroke While on Treatment With NOACs.” She also interviews Dr. Alexander Nave about “Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events.” Dr. Negar Asdaghi: Let's start with a few questions. 1) How much time do we actually save if we were to transfer all patients with suspected target vessel occlusion directly to the angiosuite and practically bypassing our current conventional imaging model? 2) What is the impact of an impaired metabolic state as measured by abnormal glucose and triglyceride tolerance tests on the risk of stroke recurrence in patients with ischemic stroke? 3) And finally, should we or should we not change the anticoagulant therapy of a patient with atrial fibrillation who suffered an ischemic stroke despite appropriate treatment with anticoagulation? We have the answers to these questions and much more in today's podcast because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2022 issue of Stroke contains a range of really stimulating articles. We have an interesting study titled "Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young," led by Dr. Amelia Boehme and colleagues from Columbia University, with its accompanying editorial on how influenza-like illness is associated with increased risk of stroke in the young and middle-aged population while vaccinations of any type is protective of this risk. In a different paper, as part of a population-based study out of Scotland, Dr. Rustam Al-Shahi Salman from University of Edinburgh and colleagues report on a positive association between the use of beta-blockers, especially propranolol, and a lower risk of cerebral cavernous malformation, or CCM, associated intracranial hemorrhage. This study's findings are very interesting and quite important, and I encourage you to review the growing literature to suggest how beta-blockers may, in fact, reduce the risk of CCM-related hemorrhages through their anti-angiogenic properties. Dr. Negar Asdaghi: Later in the podcast, I have the great pleasure of interviewing Dr. Alexander Nave from Charité University Hospital in Berlin to discuss the relationship between having an impaired metabolic state in the setting of acute stroke and the risk of ischemic stroke recurrence, as we'll review the long-awaited results of the Berlin "Cream&Sugar" study, a very catchy title. But first, with these two articles. Dr. Negar Asdaghi: Time to successful endovascular reperfusion is an important predictor of clinical outcomes in patients with acute ischemic stroke related to a large vessel occlusion. And for years, we've known that the faster we're able to open the affected artery, the better the ischemic stroke outcomes are. Correspondingly, systems of care have adapted to various requirements of this so-called rapid workflow to ensure that all necessary pre-reperfusion steps are completed as fast as possible, preferably most in parallel to one another. And if any steps are unnecessary, they're bypassed altogether. Dr. Negar Asdaghi: Despite all these modifications to date, time from conventional imaging to angiosuite arrival remains both the longest and the most variable interval in the intra-hospital workflow prior to endovascular therapy. So, it's not surprising that many recent studies have evaluated whether the current model of hospital arrival, then transfer to the scanner for imaging, then transfer to the angiosuite for endovascular therapy, can be replaced by a simpler model where, based on clinical assessment, a patient with high likelihood of having a target vessel occlusion can directly be transferred to the angiosuite, where fast stroke imaging, including CT, CT angiogram, and CT perfusion, are completed on the angiotable using the flat panel imaging technology. Dr. Negar Asdaghi: If the patient is then found to be eligible to receive reperfusion therapies, including intravenous thrombolytics, they can receive the treatments and then proceed to endovascular thrombectomy without any further delays. So, in this issue of the journal, in the study titled "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion," Dr. Raul Nogueira from Department of Neurology at Emory University and colleagues performed a systematic review and meta-analysis of published articles on this topic. So, they included seven articles for this analysis after pulling over 4000 articles using the common search engines for this meta-analysis. These articles included two single-centered European randomized controlled trials, one conducted in Germany, and the other one conducted in Spain, and five observational studies for a total of 1971 patients. The primary outcome was the odds of achieving favorable neurological recovery as defined by a modified Rankin Scale of zero to two at 90 days. Dr. Negar Asdaghi: Now, a few things to note: All studies reported door-to-puncture times, but not all reported door-to-reperfusion times or rate of successful reperfusion, and we know that these metrics are important in predicting the odds of safety and efficacy outcomes of endovascular therapy. And also it's important to note that not all details of the safety and efficacy outcome measures were reported in all of those seven studies. So, with that, here are the main findings of the meta-analysis. First off, amongst patients who were directly transferred to the angiosuite across these seven studies, the overall rate of false activation was 28%, meaning that after imaging assessment, 28% of those who were directly taken to the angiotable were not found to have a target occlusion, and as such, there was no need to further proceed to endovascular thrombectomy. And this is a practical finding of this meta-analysis as we deal with resource allocation and concerns of potentially overwhelming the neurointerventional teams. Dr. Negar Asdaghi: Now, moving on to the next finding of the study, the direct angio approach significantly reduced door-to-puncture times by a median of 30 minutes, and door-to-reperfusion times, when these metrics were available, by a median of 33 minutes as compared to the conventional imaging approach. So, bypassing conventional CT does translate into faster time metrics. These were, of course, expected findings of this meta-analysis, but nonetheless, important to quantify. But these faster time metrics did not improve the endovascular procedural outcomes, meaning that the direct to angio approach did not increase the odds of achieving a TICI 2b or better reperfusion, which is how successful reperfusion is defined, or the odds of achieving full reperfusion, meaning modified TICI 2c or greater reperfusion. Dr. Negar Asdaghi: So, it's great to get to the angiosuite fast, but that does not impact the procedural outcomes of endovascular therapy. Despite the above, the faster approach resulted in a significantly better functional independence outcome as measured by mRS Scale at 90 days, again emphasizing how important time is when it comes to endovascular outcomes. Now, the authors also performed a number of subgroup analysis in this meta-analysis, which I'd like to highlight some of them. We know that the impact of time on endovascular outcomes is more robust in the early time window. So, not surprisingly, when restricting the primary outcomes to those presenting within six hours from symptom onset, the favorable effect of direct to angio approach persisted in the early time window as well. Dr. Negar Asdaghi: Another important subgroup analysis was when restricting data to those patients who were transferred from a primary hospital to an endovascularly-capable center, the direct angio method didn't really have a significant impact on improving the primary outcome. Why is that? Let me repeat. So, when they restricted the analysis to those patients who were transferred from one hospital to an endovascularly-capable center, they did not find the same significant positive impact on endovascular outcomes in the direct to angio approach. I think the way we can explain this from a pathophysiological standpoint is that transferred patients are more likely to be slow progressors and, therefore, less likely to be impacted by delays in the workflow process as compared to the fast progressors. Dr. Negar Asdaghi: Take-home message: We've got to be fast in the fast progressors, and it's safe to assume that those who are within the first six hours after presentation are more likely to be fast progressors, and these workflow modifications are, therefore, much more robust and much more impactful in patients who present early on after their symptoms onset. And finally, in terms of safety outcomes, there were no significant differences in the rate of symptomatic intracerebral hemorrhage rate or the 90-day mortality rates either for the whole study population or when the analysis was restricted to those treated in the early time window. Dr. Negar Asdaghi: So, in summary, what we learned from this large meta-analysis is that as compared to the current conventional imaging model, the direct transfer to angio model is not only plausible and unlikely to overwhelm the interventional teams, as only less than 30% of patients in a direct method were not eligible for endovascular thrombectomy, but also this method is safe and results in significant improvements in workflow time metrics and functional outcomes. So, as the saying goes, select faster, select less, and treat more will likely be the future of endovascular therapy, particularly in the early time window. Dr. Negar Asdaghi: We know that oral anticoagulants reduce the risk of ischemic events in patients with atrial fibrillation. Nonvitamin K antagonist oral anticoagulants, or NOACs, also known as direct oral anticoagulants, or DOACs, are currently the standard of care for treatment of patients with non-valvular atrial fibrillation. Now, we have to keep in mind that although NOACs reduce the risk of ischemic stroke and systemic embolism in atrial fibrillation, they don't completely abolish the risk. So, they're not curative treatments for AFib, and patients can still experience embolic events despite appropriate treatment with these agents. In a meta-analysis of randomized trials, the residual risk of ischemic events in patients treated with NOACs was estimated at 1.4% per year, but this number is a lot lower than what is reported by real-life observational studies. Dr. Negar Asdaghi: In the large multicenter RENO study, which was published in this journal in 2019, we learned that in the setting of atrial fibrillation treated with a NOAC, a number of factors, including atrial enlargement, dyslipidemia, scoring high on the CHA2DS2-VASc score, and the use of low dose of NOACs, especially off-label low dose use of these medications, are significantly associated with increased risk of recurrent ischemic events despite treatment. But there's still a number of important questions that we routinely encounter in practice, most important of which is how to manage these patients with these so-called breakthrough ischemic events moving forward? Do we switch them to a different NOAC or go back to a vitamin K antagonist? Should we add an antiplatelet treatment to the regimen? And importantly, how do we counsel these patients and their families on their future risk of recurrent ischemic or hemorrhagic events? Dr. Negar Asdaghi: So, in the current issue of the journal, the RENO investigators, led by Dr. Maurizio Paciaroni and Valeria Caso, set out to answer some of these important questions as part of the RENO-EXTEND study, which basically followed the patients in the RENO cohort for at least 12 months, evaluating them for either recurrent ischemic or hemorrhagic events, whether occurring intra or extracranially. So, a bit about this cohort. The RENO study was a multicenter observational cohort across 43 centers in Europe and the United States, including consecutive patients with atrial fibrillation who presented to the hospital with an acute ischemic stroke despite being on a NOAC therapy. Patients were enrolled in the study only if they were compliant with their NOAC treatment and they had not missed their treatment for any reasons for greater than 24 hours prior to their index event. Dr. Negar Asdaghi: The patients were followed in the cohort and the choice of whether or not to start and timing, very importantly, for resumption of anticoagulation therapies were left to the discretion of the treating physicians. For the current paper, they analyzed 1240 patients. After the index event, 39.5%, so close to 40%, had their NOACs changed to another NOAC, mostly to a different class of NOAC. 42.5% continued with the same NOAC at the same dose. 6.7% continued with the same NOAC, but the dose was increased, and a small percentage were shifted to warfarin, that was only 4.7% of the patients. And 6.6% were shifted to low molecular weight heparin or were never prescribed oral anticoagulations after that index event for a variety of reasons, such as earlier ischemic recurrence, early hemorrhagic transformation, or early death or severe index stroke. And the overall median follow up in the study was 15 months. Dr. Negar Asdaghi: So, with that, here are the main study findings. The annual rate of the primary outcome of recurrent ischemic or hemorrhagic events, again, a reminder that these could have been intra or extracranial events, was 13.4%. The majority of these events were ischemic stroke, followed by major extracranial bleeding, then intracranial bleeding and systemic embolism. We have to note that this overall primary outcome rate is a lot higher than what was observed as part of the randomized trials of NOACs, as we noted earlier, which is an important finding of these real-life studies. Now, with regards to the factors predicting the primary outcome, having a higher CHA2DS2-VASc score and persistent hypertension were both predictive of recurrent ischemic events, whether ischemic stroke or systemic embolism. Next, the predictive factors for hemorrhagic events, either intracranial or major extracranial bleeding, included age, for each year increase in age, the odds increased by 1.1; history of major bleeding in the past; and, very importantly, a scenario that not uncommonly happens in routine practice, which is the addition of antiplatelet to a NOAC after the so-called NOAC failure. Dr. Negar Asdaghi: And finally, it turns out that changing that failed NOAC to a different agent didn't really seem to make a difference at all. As we mentioned earlier, close to 40% of patients were changed from one NOAC to another agent after the index ischemic event, and when they looked at the primary outcome, there was no difference in the rate of combined ischemic and hemorrhagic events, or the ischemic events alone, or bleeding outcomes alone, amongst patients who changed their NOAC to a different agent as compared to those who did not. The authors performed a number of subanalyses to see whether a particular strategy, for example, a switch from a particular class of NOACs to another class, or change in dosage, or NOAC to warfarin change, may be more or less beneficial in reducing the primary outcome, and there was really no difference between any of these strategies with the exception of one group. Dr. Negar Asdaghi: It turns out that the cumulative risk of ischemic and hemorrhagic events were a lot higher in those 6.6% of patients in whom NOAC treatment was changed to low molecular weight heparin injection. But I think one should consider this observation as hypothesis generating. First off, it was just a very small percentage of patients in this study that actually did go through this switch. And also we should note that in practice, we reserve a switch to low molecular weight heparin injection in only special cases. Some examples would be patients in whom there's a consideration of a hypercoagulable state, whether cancer related or not. But regardless, I think what we learned from this finding is that the patients in whom low molecular weight heparin injection is considered after a NOAC or an anticoagulant failure are likely very high risk patients for recurrent thromboembolic and hemorrhagic events. Dr. Negar Asdaghi: So, in summary, we learned a number of important lessons from RENO-EXTEND study. Number one, patients with atrial fibrillation presenting with a breakthrough ischemic stroke, despite treatment with NOAC, represent a high-risk group of patients who continue to be at a substantial risk for recurrent events, mostly ischemic, but also hemorrhagic. And this substantial risk was actually over 10% in the current study. Number two, we also learned that various strategies of changing the dose or class of anticoagulants don't seem to have much, if any, benefit in reducing the recurrent event outcomes. And finally, the addition of antiplatelet to oral anticoagulant therapies in this situation is not a good idea. This strategy gets us more in trouble and can increase the risk of bleeding and confers practically no benefits. Finally, these are the types of patients in whom we may have to consider other treatment options, such as left atrial appendage closure, and I'm sure we'll hear more on this in the future. Dr. Negar Asdaghi: Having an abnormal lipid profile has long been recognized as a risk factor for development of vascular disorders, particularly leading to atherosclerosis, but this association varies for the different components of the lipid panel and is most robust for elevated low density lipoprotein cholesterol levels, or LDL, causing various vascular disorders. Amongst patients with ischemic stroke and TIA, randomized trials have also shown that lowering LDL can reduce the risk of major cardiovascular events, including the risk of ischemic stroke, but the connection between elevated triglyceride levels and the risk of recurrent ischemic stroke is less clear. Moving from lipids to sugar, the presence of uncontrolled diabetes increases the risk of stroke by two to five folds, depending on the patient population studied and coexistence of other risk factors. In contrast, impaired glucose tolerance, which is an intermediate metabolic state between normal glucose tolerance and diabetes, has also been found to be associated with an increased risk of stroke in patients with coronary artery disease, but this association is less clear amongst patients with ischemic stroke. Dr. Negar Asdaghi: In clinical practice, fasting blood glucose and lipid profiles are routinely measured post-stroke, but we put a greater emphasis on the elevated LDL and hemoglobin A1C levels, and, in general, pay less attention, if any, to other metabolic derangements, including the impaired glucose tolerance state or even abnormal triglyceride levels. So, the question is, what is the impact of these metabolic derangements on the risk of stroke recurrence amongst patients presenting with ischemic stroke? In the current issue of the journal, in the study titled "A Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin 'Cream&Sugar' Study," we learn about these important associations. Joining me now is the first author of this paper, Dr. Alexander Nave. Dr. Nave is a neurologist and clinician scientist at Charité University Hospital in Berlin. He leads a junior research group as part of the Center of Stroke Research in Berlin and has a special interest in stroke rehabilitation and cardioembolic risk factors of stroke. Good morning, Alex, from Miami. Good afternoon to you in Berlin. Thank you for joining us. Welcome to our podcast. Dr. Alexander Nave: Hi, thank you very much. I'm very happy to be with you. Dr. Negar Asdaghi: All right. Let's go over the background of what we knew on the association between elevated triglyceride levels and the risk of recurrent stroke. Dr. Alexander Nave: Sure. So, as you pointed out earlier, diabetes and hypercholesterolemia are well established risk factors for first and recurrent ischemic stroke. However, for triglyceride levels, this association is less well understood and somewhat inconclusive. So, prior large epidemiological studies of the healthy population from the U.S. and from Denmark have shown an independent association of triglyceride levels in the risk of vascular events, including ischemic stroke. This association was actually stronger for non-fasting triglycerides levels compared to fasting triglycerides levels. In the ischemic stroke population, however, there were only a few investigations with conflicting results. So, the SPARCL trial, for example, which was a large secondary prevention stroke trial with more than 3000 stroke patients, showed that triglyceride levels were associated with major cardiovascular events, but not with recurrent ischemic stroke. So, therefore, we designed the Berlin “Cream&Sugar” study to investigate the association of postprandial triglyceride levels following an oral triglyceride tolerance test with recurrent vascular risk. Dr. Negar Asdaghi: So, let me just summarize. From SPARCL, actually, we knew that an increased level of triglycerides were associated with increased risk of development of cardiovascular events, so things such as coronary artery events and so on, but not an increased risk of stroke. And that's where you come in with the new study, the Berlin “Cream&Sugar” study. Now, before we talk about the study, can you tell us a little bit about the tests that were done, the oral triglyceride and glucose tolerance tests? Dr. Alexander Nave: Absolutely. So, both tests eventually help us to evaluate the glucose and lipid metabolism of a patient. So, the OGTT, the oral glucose tolerance test, as most of the listeners probably know, is a test that helps us to assess the ability of the patient to metabolize glucose after receiving a drink with a standard dose of 75 grams of glucose. The blood glucose levels after one hour and two hours then help us to diagnose diabetes or pre-diabetic state of the patient. So, we're not only evaluating the fasting state, but we can also quantify the body's response to a glucose challenge. And as an equivalent, the OTTT, the oral triglyceride tolerance test, will test the ability of a patient to metabolize triglycerides after oral ingestion of a lipid challenge, which is usually a certain amount of fat. However, this test is less well studied and without any standardized diagnostic criteria so far. And in contrast to the OGTT, the OTTT has not been tested in the stroke population so far. Dr. Negar Asdaghi: So, we're not just looking at those metrics of fasting sugar or fasting lipids and triglycerides specifically, we're looking at the patient's ability to metabolize glucose or triglyceride levels. So, now, with that understanding, can you tell us a little bit about the methodology of the study? Dr. Alexander Nave: Yes, of course. So the Berlin “Cream&Sugar” study was a prospective observational study recruiting acute stroke patients between 2009 and 2017 at the Charité University Hospital in Berlin. And we included first-ever ischemic stroke patients within three days to seven days after onset of stroke, and all patients received a sequential OTTT OGTT. So, all recruited patients received fasting blood sampling in the morning before taking the OTTT with 250 cc of cream, which corresponds to 30% of fat intake. So, all patients without known diabetes mellitus additionally had the OGTT with 75 grams of glucose starting three hours after the OTTT. Dr. Alexander Nave: And all patients received consecutive blood tests at three hours, four hours, and five hours after start of the OTTT to determine the course of glucose and triglyceride levels in the blood. And after one year, we performed follow up of all patients. The primary outcome was recurrent fatal or non-fatal ischemic stroke, and secondary outcome was a composite endpoint of recurrent vascular events, including ischemic stroke, TIA, myocardial infarction, and coronary revascularization, as well as cardiovascular death. And we compared patients with high versus low fasting and nonfasting triglyceride and glucose levels, respectively, using Cox regression analysis. Dr. Negar Asdaghi: Okay. 250 cc of cream and 75 grams of sugar right after a stroke. Was it challenging to recruit patients? Dr. Alexander Nave: Yes, that was a task. And we did experience some difficulties during the course of the study. It was not easy to ask a patient to drink a glass of cream during the first week after suffering from a stroke, obviously. In fact, a substantial number of patients eventually did not participate or did not complete the OTTT. However, in our study, we showed that performing a sequential OGTT OTTT within seven days after stroke was feasible. Approximately 10% of patients reported only minor adverse events such as nausea, diarrhea, and bloating. But with regards to the study population, overall, we enrolled 755 patients, 523 have completed the challenge and entered follow up. So, considering the fact that we had some difficulties in recruitment, was not surprising that we predominantly ended up with minor ischemic stroke patients, considering that we did not include patients with dysphagia or patients that were not able to give informed consent in the early phase after stroke. The median NIHSS was one with an interquartile range of zero to three. And, as I mentioned previously, this was because patients with impaired swallowing could not be included into the study. Dr. Negar Asdaghi: Okay. So, 750 patients within a week after their stroke, majority of them, as you mentioned, had mild ischemic events, were enrolled, and then they underwent sequential OTTT and OGTT tests. And then they were followed for a year for the primary outcomes. Now I think we're ready to hear the primary results. Dr. Alexander Nave: Sure. So, overall, 54 patients, 10% of the total population, reached a study endpoint within one year follow up. 31 patients experienced recurrent ischemic stroke within one year. So, when we compared the highest quartiles of triglyceride levels to the lowest quartiles, neither fasting nor postprandial triglyceride levels were associated with recurrent stroke. Similarly, fasting triglyceride levels were not associated with major cardiovascular events one year after stroke. Surprisingly though, higher postprandial triglycerides, measured at five hours after OTTT, were significantly associated with a lower risk for recurrent vascular events. The hazard ratio was 0.42, and the confidence interval 0.18 to 0.95. So, regarding glucose levels, on the other hand, we found no associations between glucose levels and recurrent vascular risk at all. Dr. Negar Asdaghi: Interesting. So, before I ask you what your takeaway is from all of this, the first question is the 10% rate of primary outcome. Were you at all surprised by this? This seems quite high for the recurrent rate of vascular events after the first year after ischemic stroke and TIA. Dr. Alexander Nave: Well, actually, when the “Cream&Sugar” study was designed, we expected the recurrent event rate to be even higher, approximately 10% of recurrent stroke events within one year and not 10% recurrent vascular events as a composite outcome. But as we know from previous registries, such as the TIA registry, the recurrent risk of vascular events after TIA and minor stroke is much lower now. So, I think with the reported 7% of recurrent stroke events, we're actually quite in line with the reports of the TIA registry, considering the fact also that we had no TIA patients enrolled in our study and had quite a high proportion of patients with large artery atherosclerosis as well as atrial fibrillation. Dr. Negar Asdaghi: So, thank you. This is a grim reminder that ischemic stroke patients remain at high risk of having recurrent vascular events. Alex, what should be our top two takeaway messages from your study? Dr. Alexander Nave: So, first, I think a sequential OTTT OGTT probably does not contribute a lot to future vascular risk stratification in ischemic stroke patients. So, I think all patients and carers can be relieved. There's no need to implement an OTTT into routine clinical care. However, based on our results, I think further studies are necessary and needed to better understand the importance of glucose and lipid metabolism in patients after acute ischemic stroke. And eventually we might figure out some nice information how we can improve risk prediction. Dr. Negar Asdaghi: So, it's good to know that we don't have to ask patients to drink a lot of cream after stroke. Can you tell us a little bit about the future of the Berlin “Cream&Sugar” study group? What are the next steps for the authors and the study group? Dr. Alexander Nave: Absolutely. Well, since there's no urgent need to start another large study soon, I think it would be reasonable to get our data and merge it with datas from other groups who also investigated the role of an OTTT in cardiovascular risk cohorts, also to increase power and detect some other signals. And we want to have a more detailed look at the variability of triglycerides and glucose levels following sequential OTTT OGTT. So, not only go into the absolute levels that you can measure at certain time points, but also how much these parameters fluctuate over time. Dr. Negar Asdaghi: To Alexander Nave, it's been a pleasure interviewing you on the podcast today. We look forward to covering more of your work in the future. Dr. Alexander Nave: Thank you very much. It was a pleasure to talk to you. Dr. Negar Asdaghi: And this concludes our podcast for the August 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three topical reviews, from “Strategies for Maintaining Brain Health: The Role of Stroke Risk Factors Unique to Elderly Women” to “Ethical Considerations in Surgical Decompression for Stroke.” These articles summarize a large body of evidence, which I encourage you to review. And before we end our August podcast, I'd like to take a moment to recognize the incredible dedication and hard work of our medical students and fellows, especially the young doctors who are just starting their training this year. Dr. Negar Asdaghi: And if you happen to be one of those young doctors who is listening to our podcast in one of those sleepless on-call nights, I want to recount the story of Dr. Carl David Anderson, who won the Nobel Prize in physics for his discovery of the first particle of antimatter known as positron on August 2, 1932. A positron is actually the identical twin of the well-known negative electron, and its discovery in the 1930s truly changed our understanding of the origin of the universe, and it's practically impacted all aspects of science, not to mention it's impacted medicine and medical imaging. But the moral of the story lies in the fact that on August 2, when Anderson announced his discovery, he was a post-doctoral fellow himself, hadn't even graduated yet. So, if you are such a trainee, I hope you know that your hard work, combined with that incredible scientific inquisition, has the potential to change our understanding of the universe. And what better way to do this? You guessed it, than staying alert with Stroke Alert. Dr. Negar Asdaghi: 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, visit AHAjournals.org.

NOACs x cirrose hepática

Cardiopapers

Play Episode Listen Later Jul 15, 2022 2:24

NOACs x cirrose hepática by Cardiopapers

noacs cardiopapers

What does the XARENO study mean for our patients with atrial fibrillation and kidney disease?

Play Episode Listen Later Jun 8, 2022 15:10

In this podcast, Dr Manesh Patel, Professor Reinhold Kreutz and Dr Andrew Steele discuss the results of the XARENO study and its implications for patients with AF and chronic kidney disease. This group of experts share their insights on how cardiologists and nephrologists can work most effectively together in multi-disciplinary teams to provide optimal care for these patients. The views and opinions expressed throughout this podcast are those of the speakers based on their expertise and do not necessarily reflect those of Bayer AG. Further details: • The paper on the rationale and design of the XARENO study can be found here: https://journals.viamedica.pl/kardiologia_polska/article/view/86346 • The XARENO abstract presented at ACC 2022 is available here: https://www.jacc.org/doi/10.1016/S0735-1097%2822%2901192-5 • The results of XARENO presented at AHA 2020 can be accessed here: https://www.ahajournals.org/doi/10.1161/circ.142.suppl_3.13927 • Further information on the XARENO trial can be found on the clinicaltrials.gov page here: https://clinicaltrials.gov/ct2/show/study/NCT02663076 • The paper on the ANTENNA study can be found here: https://www.sciencedirect.com/science/article/pii/S0167527322001905 • The 2021 ESC guidelines for the diagnosis and management of atrial fibrillation featuring the ABC pathway for AF treatment are available here: https://academic.oup.com/eurheartj/article/42/5/373/5899003 • Find the 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation here: https://www.ahajournals.org/doi/10.1161/CIR.0000000000000665 • The EHRA practical guide on the use of NOACs in patients with atrial fibrillation can be accessed here: https://academic.oup.com/europace/article/23/10/1612/6247378 • For anticoagulant dosing information, see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf) and warfarin (https://www.medicines.org.uk/emc/product/3064/smpc) and the Canadian label for rivaroxaban (https://pdf.hres.ca/dpd_pm/00059600.PDF) Shownotes: MA-M_RIV-ALL-1212-1 Recording: MA-M_RIV-ALL-1205-1

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EHRA 2022 - Expert Podcast With John Camm And Keith Fox

Play Episode Listen Later Mar 29, 2022 22:30

This podcast is a follow-up to Bayer's symposium at EHRA 2022 ‘What if? Protecting your patients with AF from stroke, no matter their journey.' In this discussion, Professor John Camm and Professor Keith Fox provide further insight as to why patients with AF undergoing PCI need such close attention when choosing an antithrombotic regimen. They also explore additional considerations for the management of patients with AF undergoing elective PCI. Finally, the experts provide their perspectives on how patients with AF undergoing catheter ablation can be best protected from cardioembolic stroke. The views and opinions expressed throughout this podcast are those of the speakers based on their expertise and do not necessarily reflect those of Bayer. Further details: • Read the 2020 ESC guidelines for the management of atrial fibrillation here: https://academic.oup.com/eurheartj/article/42/5/373/5899003 • The 2020 ESC guidelines for the management of acute coronary syndromes can be found here: https://academic.oup.com/eurheartj/article/42/14/1289/5898842 • Find the 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation here: https://www.ahajournals.org/doi/10.1161/CIR.0000000000000665 • The EHRA practical guide on the use of NOACs in patients with atrial fibrillation can be accessed here: https://academic.oup.com/europace/article/23/10/1612/6247378 • The papers for the trials investigating NOACs in patients with AF undergoing PCI can be found here for rivaroxaban (https://www.nejm.org/doi/full/10.1056/nejmoa1611594), apixaban (https://www.nejm.org/doi/full/10.1056/NEJMoa1817083), edoxaban (https://www.sciencedirect.com/science/article/abs/pii/S0140673619318720) and dabigatran (https://www.nejm.org/doi/full/10.1056/nejmoa1708454) • The findings from the Japanese study of rivaroxaban monotherapy versus rivaroxaban plus clopidogrel, the AFIRE trial, is available here: https://www.nejm.org/doi/full/10.1056/nejmoa1904143 • Data from the COMPASS trial can be accessed here: https://www.nejm.org/doi/full/10.1056/nejmoa1709118 • For anticoagulant dosing information, see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-productinformation_en.pdf) and warfarin (https://www.medicines.org.uk/emc/product/3064/smpc) • For antiplatelet dosing information, see the European labels for clopidogrel (https://www.ema.europa.eu/en/documents/product-information/plavix-epar-productinformation_en.pdf), prasugrel (https://www.ema.europa.eu/en/documents/productinformation/efient-epar-product-information_en.pdf) and ticagrelor (https://www.ema.europa.eu/en/documents/product-information/brilique-epar-productinformation_en.pdf) • The European label for pantoprazole can be accessed here: https://www.ema.europa.eu/en/documents/product-information/pantoloc-control-eparproduct-information_en.pdf Show notes: MA-M_RIV-ALL-1173-1 Recording: MA-M_RIV-ALL-1172-1

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Treatment of cancer-associated thrombosis: What is the evidence for rivaroxaban?

cancer treatments cat ash american society papers supplement caravaggio callisto hematology clot thrombosis cosimo jco rivaroxaban noacs casta diva

Play Episode Listen Later Feb 22, 2022 18:53

In this episode, Professor Cihan Ay and Dr Jeffrey Weitz and provide an overview of the evidence base for the use of rivaroxaban in CAT, including randomized controlled clinical trials, real-world studies and data regarding patient satisfaction and quality of life. Further details: • The paper on the CLOT trial investigating the efficacy of dalteparin versus oral anticoagulation in preventing recurrent thrombosis in patients with cancer is available here: https://www.nejm.org/doi/full/10.1056/nejmoa025313 • Papers on the five randomized controlled trials comparing NOACs with dalteparin for the treatment of CAT can be accessed here: SELECT-D and CASTA DIVA with rivaroxaban (https://ascopubs.org/doi/10.1200/JCO.2018.78.8034 and https://journal.chestnet.org/article/S0012-3692(21)04079-4/fulltext), ADAM VTE and Caravaggio with apixaban (https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14662 and https://www.nejm.org/doi/full/10.1056/NEJMoa1915103) and Hokusai VTE Cancer with edoxaban (https://www.nejm.org/doi/full/10.1056/NEJMoa1711948) • Information on the CALLISTO programme can be found here: https://onlinelibrary.wiley.com/doi/10.1002/rth2.12327 • Details on the COSIMO study are available here: https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-018-0176-2 and https://ashpublications.org/blood/article/134/Supplement_1/2161/427953/Baseline-Characteristics-and-Clinical-Outcomes • Information on the CONKO-011 study can be accessed here: https://abstracts.isth.org/abstract/improved-patient-reported-treatment-satisfaction-with-rivaroxaban-as-compared-to-low-molecular-weight-heparins-for-cancer-patients-with-acute-venous-thromboembolism-results-from-the-conko-011-trial/ and https://clinicaltrials.gov/ct2/show/NCT02583191 • Study information for the OSCAR studies can be found here for OSCAR-US (https://clinicaltrials.gov/ct2/show/NCT04979780), OSCAR-UK (https://clinicaltrials.gov/ct2/show/NCT05112666) and OSCAR-SE (https://clinicaltrials.gov/ct2/show/NCT05150938) • The abstract of the OSCAR-US presentation at ASH 2021 is available here: https://ash.confex.com/ash/2021/webprogram/Paper151566.html • The American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer guidelines can be accessed here: https://ashpublications.org/bloodadvances/article-lookup/doi/10.1182/bloodadvances.2020003442

Practical Insights for High-Risk Patients From the 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation

Keeping Current CME

Play Episode Listen Later Feb 22, 2022 29:56

Join EHRA 2021 guideline editors as they summarize the practical recommendations on the use of NOACs in AF. Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/968504?src=mkm_podcast_addon_968504

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CardioPoint (2): NOAC Monitoring, Do NOACs Need Monitoring?

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Play Episode Listen Later Jan 18, 2022 4:50

A Brief Description on Practical Points in Anticoagulation

CardioPoint (3): NOACs in Elderly

elderly anticoagulation noacs

Play Episode Listen Later Jan 18, 2022 6:35

A Brief Description on Practical Points in Anticoagulation

CardioPoint (5): NOACs in CKD

Play Episode Listen Later Jan 17, 2022 6:17

A Brief Description on Practical Points in Anticoagulation

anticoagulation noacs

CardioPoint (9): Once vs. twice-daily NOACs and adherence considerations

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Play Episode Listen Later Jan 17, 2022 1:36

A Brief Description on Practical Points in Anticoagulation

Evolving Cardiovascular Risk: Your Patient's Past, Present and Future

Play Episode Listen Later Jan 5, 2022 28:41

This podcast is a follow up to Bayer's symposium at ESC 2021 ‘Evolving Cardiovascular Risk: Your Patient's Past, Present and Future'. Following on from the discussions at that meeting, Professor Craig Coleman and Professor Roxana Mehran provide further expert perspectives on the importance of considering your patient's kidney function when they have atrial fibrillation, and discuss how to protect patients from the devastating effects of stroke. Professor Manesh Patel and Dr Rónán Collins then focus on stroke prevention in older patients with atrial fibrillation and highlight the fascinating studies that caught their eye among the ESC scientific programme. Further details: • Read the 2020 ESC guidelines for the management of atrial fibrillation here: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Atrial-Fibrillation-Management • Find the 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation here: https://www.ahajournals.org/doi/10.1161/CIR.0000000000000665 • The EHRA practical guide on the use of NOACs in patients with atrial fibrillation can be accessed here: https://academic.oup.com/europace/article/23/10/1612/6247378 • Real-world evidence from the ANTENNA study showing the benefit of rivaroxaban versus warfarin for the treatment of renal decline in patients with atrial fibrillation is available here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=104597 • The study by Bonand et al. demonstrating the benefits of NOACs versus vitamin-K antagonists in patients older than 80 years with atrial fibrillation can be seen here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=107076 • Data from the EMIR study regarding treatment of elderly patients with atrial fibrillation with rivaroxaban can be seen here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=107122 • The study by Lee et al. confirming the positive net clinical benefits of NOACs in elderly patients with high bleeding risk and atrial fibrillation is available here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=104607 • Data presented by Chao et al. on the impact of off-label dosing of NOACs in elderly patients can be found here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=105312 • Data from the ETNA-AF study can be accessed here: https://esc2021-abstract.medicalcongress.online/mediatheque/media.aspx?channel=103467&mediaId=105275 • The original publication of the ARISTOTLE trial can be found here: https://www.nejm.org/doi/full/10.1056/nejmoa1107039 • Access to the ROCKET AF original publication can be found here: https://www.nejm.org/doi/full/10.1056/nejmoa1009638 • The XANTUS primary publication can be found here: https://academic.oup.com/eurheartj/article/37/14/1145/2466063 • For anticoagulant dosing information, see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf) and warfarin (https://www.medicines.org.uk/emc/product/3064/smpc) Show notes: MA-M_RIV-ALL-1126-1 Recording: MA-M_RIV-ALL-1125-1

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NOACs for the treatment of VTE: How can we improve the patient experience?

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Play Episode Listen Later Nov 1, 2021 12:41

In this episode, Professor Stavros Konstantinides and Professor Ander Cohen discuss contemporary guidance on how the patient experience can be improved for those receiving non-vitamin K antagonist oral anticoagulants (NOACs) for venous thromboembolism (VTE) without concurrent cancer. Further details: • The 2019 European Society of Cardiology (ESC) guidelines for the diagnosis and management of acute pulmonary embolism, developed in collaboration with the European Respiratory Society (ERS), can be found here: https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz405 • The American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease can be found here: https://journal.chestnet.org/article/S0012-3692(15)00335-9/fulltext • The summary of product characteristics for rivaroxaban can be found here: https://www.medicines.org.uk/emc/product/2793/smpc#gref • The summary of product characteristics for apixaban can be found here: https://www.medicines.org.uk/emc/product/2878/smpc#gref • The summary of product characteristics for dabigatran can be found here: https://www.medicines.org.uk/emc/product/4703/smpc#gref • The summary of product characteristics for edoxaban can be found here: https://www.medicines.org.uk/emc/product/6905#gref

Truques e dicas para a vacinação (covid-19) de doentes tratados com Noac

Play Episode Listen Later May 27, 2021 3:27

Novo guia prático 2021 de utilização de Noacs

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Noacs em doentes com extremo de peso

Play Episode Listen Later May 27, 2021 5:28

Novo guia prático 2021 de utilização de Noacs

novo peso extremo doentes noacs

É seguro utilizar NOACs em doentes com próteses biológicas?

Play Episode Listen Later May 27, 2021 4:18

Ensaio clínico RIVER (Guimaraes et al. N Engl Med 2020) Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2029603

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Como utilizar Noacs na “Fa valvular”?

Play Episode Listen Later May 27, 2021 5:22

Novo guia prático 2021 de utilização de Noacs

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Truques de utilização de Noacs em doentes com insuficiência renal grave e terminal

Play Episode Listen Later May 27, 2021 6:56

Novo guia prático 2021 de utilização de Noacs

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Utilização de Noacs em doentes idosos, frágeis ou com risco de quedas

Play Episode Listen Later May 27, 2021 7:44

Novo guia prático 2021 de utilização de Noacs

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Utilização de Noacs em doentes com trombocitopenia

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Play Episode Listen Later May 27, 2021 5:08

Novo guia prático 2021 de utilização de Noacs

Circulation May 4, 2021 Issue

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Play Episode Listen Later May 3, 2021 28:01

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, it's another double feature Tuesday and today we get to discuss two articles. One, some insights from the CREDENCE trial. And second, another article about left atrial appendage closure devices, some results from the PINNACLE FLX trial. But before we get to those, how about we grab a cup of coffee and dive into some of the other really interesting articles in this issue? Would you like to go first? Dr. Carolyn Lam: I would, because this next paper, right up your alley and I'm sure you'll like it. But first, we talk about mitral valve prolapse. Now, we know that's a frequent disease that can be complicated by mitral regurgitation, heart failure, arterial embolism, rhythm disorders, and death. Left ventricular replacement myocardial fibrosis is a marker of maladaptive remodeling and has been described in patients with mitral valve prolapse. However, the implications of this finding remain scarcely explored. So these authors, led by Dr. [Le] Tourneau from Hôpital Laennec in France, aimed at assessing the prevalence, pathophysiological and prognostic significance of left ventricular replacement myocardial fibrosis through late gadolinium enhancement by cardiac magnetic resonance in 400 patients with mitral valve products. I bet you like that, right Greg? Dr. Greg Hundley: Oh my gosh Carolyn, not only a favorite topic of cardiovascular magnetic resonance, but this is a really large patient population with mitral valve prolapse that underwent CMR. So tell us, what did they find? Dr. Carolyn Lam: So replacement myocardial fibrosis was observed in 110 patients, so that's 28% of the patients. It was associated with mitral valve apparatus alterations, left ventricular remodeling, and ventricular arrhythmia. The ventricular arrhythmias were more frequent in patients with replacement fibrosis, but were not associated with the grade of mitral regurgitation. In patients with trace or mild mitral regurgitation, the presence of replacement myocardial fibrosis was nonetheless associated with specific mitral valve apparatus alteration at normal left ventricular dilatation, not explained by volume overload and ventricular arrhythmias, suggesting the presence of a mitral valve prolapse-associated cardiomyopathy. Dr. Greg Hundley: Wow Carolyn, really interesting. So the late gadolinium enhancement and the evidence therefore of replacement myocardial fibrosis that was identified by CMR, maybe this particular study is suggesting that we might want to integrate that into the clinical workup of patients with mitral valve prolapse. Very interesting work, and great job on that fantastic CMR presentation. I must say, got to recruit you into the club. Dr. Greg Hundley: Well, my next paper is another wonderful paper from the world of basic science and it comes from Dr. Douglas Lewandowski at the Ohio State University College of Medicine. So Carolyn, the failing heart is energy starved with impaired oxidation of long chain fatty acids at the level of reduced carnitine palmitoyltransferase-1, or CPT-1, activity at the outer mitochondrial membrane. Recent work shows that elevated ketone oxidation and failing hearts as an alternate carbon source for oxidative ATP generation. So Carolyn, these authors hypothesized that another short chain carbon source, short chain fatty acids that bypass CPT-1, could similarly support energy production in failing hearts. Dr. Carolyn Lam: Wow. Okay, so what did they find? Dr. Greg Hundley: So Carolyn, the failing heart oxidizes short-chain fatty acids more readily than ketones, with short-chain fatty acids also displacing long-chain fatty acid oxidation to somewhat of a greater extent. So in particular, the short-chain fatty acid butyrate has a higher affinity for entry into mitochondrial oxidation at the enzyme, short-chain Acyl-CoA dehydrogenase than does the ketone 3-hydroxybutyrate at the hydroxy butyrate dehydrogenase and then also through the respective downstream metabolic pathways for each substrate. So Carolyn, failing hearts of rats and humans have increased levels of Acyl coenzyme A synthetase medium chain three enzyme, which can also oxidize short-chain fatty acids to enhance butyrate oxidation. Dr. Carolyn Lam: Wow, that really is interesting. I can't say that I would have predicted that result. So could you give us a clinical implication? Dr. Greg Hundley: You bet, Carolyn. A lot of basic science here. So here's I think what we can take home, and what we learned. So while ketones have been sought as a potential supplemental fuel to remedy the impaired oxidative metabolism of the failing heart, this study shows that failing hearts preferentially oxidize short-chain fatty acids over ketones and short-chain fatty acids may prove to be a more efficient energy source during pathological stress. Dr. Greg Hundley: Next, novel alterations in metabolic pathways, favoring short-chain fatty acid oxidation in the failing heart occur in patients with non-ischemic cardiomyopathy. Then finally, circulating ketones are not a unique, super fuel beyond the ability to bypass the inhibition of long-chain fatty oxidation in the failing heart, as do the short chain fatty acids. Dr. Carolyn Lam: Thanks, I like the way you broke down the clinical implications. Well, Greg, I've got a question for you. Have you ever thought that statins may do more than lower cholesterol, but depending on what you eat? Dr. Greg Hundley: Oh wow, Carolyn. We always hear about the pleiotropic effects of statins, but I never really thought that could depend on what you eat. Tell me, so what did these authors investigate? Dr. Carolyn Lam: Yeah, so this next paper is so interesting. It's from Dr. Hu from Huazhong University of Science and Technology in Wuhan, China and colleagues, who present a novel perspective on the story of the pleiotropic effects of statins, exactly like you said, Greg. They started with the premise that statins exert pleiotropic or cholesterol-independent effects by reducing geranylgeranyl pyrophosphate production. I'm not going to keep saying that, so geranylgeranyl pyrophosphate or GGPP, is how I'm going to refer to it. Dr. Carolyn Lam: So they developed a sensitive technique to quantify dietary GGPP, and conducted proteomics, RT-PCR screening, and western blot, to determine signaling cascades, gene expression, protein-protein interaction, and protein-membrane trafficking in wild-type and transgenic rats, focusing on models of pulmonary hypertension, given their interest in the potential therapeutic efficacy of statins in pulmonary arterial hypertension. Dr. Greg Hundley: Interesting, Carolyn. Really complex and sophisticated. So what did they find? Dr. Carolyn Lam: Okay, listen up. Red meat and soybean have a high content of GGPP and their ingestion increases GGPP plasma levels, but reduces the effects of statins in rat models of pulmonary hypertension. Ingestion of garlic extracts, rich in methyl-L-phenyl sulfonate, which is a natural inhibitor of GGPP production, decreases GGPP bioavailability, and rescues statin effects in pulmonary arterial hypertension models. So consequently, first of all, diet may influence the cholesterol-independent effects of statins and the data really raise a provocative question of whether populations in which the typical diet contains high amounts of soybeans of beef may benefit less from statins. All this is discussed in an elegant editorial by Dr. Thomas Eschenhagen from Germany, who really ends with saying the present study should be considered hypothesis-generating and stimulate retrospective analysis of clinical registries and existing large interventional trials to either validate or refute this hypothesis. Whatever the outcome, the study is a nice example of thorough scientific underpinning of the widely held maxim that we are what we eat. Dr. Greg Hundley: Oh, absolutely Carolyn. I think next time with my spaghetti, I'll have the- Dr. Carolyn Lam: Garlic. Dr. Greg Hundley: ... sauce with the garlic, but I won't add the red meats. Especially if I'm taking a statin. Dr. Carolyn Lam: Oh, that's what I was afraid you might say. Oh well, let me tell you about other papers in this issue. There's an ECG challenge by Dr. Del-Carpio Munoz and entitled A Carousel ECG Confusion. There's an on my mind paper by Dr. Hammond, on the importance of shared decision making for return to play after COVID-19. Dr. Greg Hundley: Great, Carolyn. So, in the mailbag, there's a really nice research letter from Dr. Robert-Ebadi evaluating the impact of the age-adjusted D-dimer cutoff to exclude pulmonary embolism. It's from a multinational prospective real-life study or the RELAX-PE study. Well Carolyn, it's another double feature Tuesday. How about we get off to understand a little bit more about those insights from the CREDENCE trial, and then also left atrial appendage closure devices? Dr. Carolyn Lam: All right, come on with your garlic breath. Dr. Greg Hundley: Well listeners, we are onto our feature discussions and we are very fortunate, we're going to have two feature discussions. Our first feature really addresses high blood pressure. And we have with us today, Dr. Brendan Neuen from the George Institute of Global Health in Sydney, New South Wales, Australia. And our own associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern in Dallas, Texas. Welcome to you both. Brendan, we're going to start with you. Could you describe the hypothesis that you wanted to test and what was your study population and your study design? Dr. Brendan Neuen: Well, thanks Greg. In this study, what we wanted to assess was the blood pressure lowering effects of the SGLT-2 inhibitor canagliflozin in people with type two diabetes and chronic kidney disease. The reason we thought that this is important is because what we know about the blood pressure lowering effects of these drugs is largely based on people with normal kidney function, with relatively less data in people with chronic kidney disease. So we aim to assess both the blood pressure lowering effects of SGLT-2 inhibition in chronic kidney disease, as well as treatment effects by baseline blood pressure and other blood pressure defined variables. This was conducted in the CREDENCE trial, which was a large primary renal outcome trial of the SGLT-2 inhibitor, canagliflozin, which enrolled about 4,400 people with type two diabetes and chronic kidney disease with a urine albumin to creatinine ratio greater than 300 milligrams per gram and a GFR greater than 30 at enrollment. This was a high risk hypertension population, about 30% of patients had apparent treatment resistant hypertension, about 60% of people had a GFR less than 60 and about 20% of people were on four or more blood pressure lowering agents. So really high burden of hypertension in the CREDENCE trial. Dr. Greg Hundley: Very good. Tell us a little bit about that design. So is this a randomized trial? Dr. Brendan Neuen: So CREDENCE was an event-driven randomized, double blind, placebo controlled, international trial. It was the first primary renal outcome trial of an SGLT-2 inhibitor, the primary results of which were reported in the New England journal in 2019. What this trial did, was it randomized participants, as I mentioned, with a GFR of greater than 30 and significant albuminuria and type two diabetes to either canagliflozin 100 milligrams or matching placebo in a one-to-one ratio with primary outcome overall of doubling of serum creatinine, kidney failure, cardiovascular or renal death. The trial was conducted in several, I think, 20 or 30 countries overall and enrolled at approximately 4,400 people, with participants followed for a median of about two and a half years. Dr. Greg Hundley: Excellent. So Brendan, tell us, what did you find? Dr. Brendan Neuen: So we found a couple of important findings with regards to blood pressure. Firstly, what we found was that canagliflozin reduced systolic blood pressure by about three and a half millimeters of mercury in the overall trial population. But most importantly, this blood pressure lowering effect was consistent across the number of blood pressure defined subgroups, including in people on multiple numbers of blood pressure lowering agents. So irrespective of the number of blood pressure lowering agents at baseline, and also irrespective of a history of apparent treatment-resistant hypertension at baseline, that was important. We also, secondly, found that the blood pressure lowering effective SGLT-2 inhibition was present very early at the first trial visit at three weeks. This effect was sustained over the duration of the trial. Dr. Brendan Neuen: Thirdly, we also found that canagliflozin reduced the risk of kidney failure and cardiovascular events, regardless of the number of blood pressure lowering agents at baseline and regardless of blood pressure, history of resistant hypertension. Finally, there is this often important question of how do these drugs reduce the risk of kidney failure and heart failure. So we did a mediation analysis, looking at to what extent the blood pressure lowering effect of this drug explains the treatment effect on these important outcomes. We found that only about less than 10% of the treatment effect on kidney failure and cardiovascular events was explained by blood pressure lowering. Dr. Greg Hundley: Very interesting and strong, powerful results. Well, now we're going to turn listeners to our associate editor, Dr. Wanpen Vongpatanasin. Wanpen, I know you see a lot of papers come across your desk at circulation, really focused on blood pressure and its lowering. What struck you about this paper, and then how do you put into context the results that Brendan just describe for us with all the other results that you see in new blood pressure lowering strategies? Dr. Wanpen Vongpatanasin: Yes, so I think this is very important study and add to a body of literature showing that the canagliflozin, like many SGLT-2 inhibitors, inducing significant lowering of blood pressure. If anything, because CREDENCE is not designed to be hypertension study the effects of blood pressure lowering my even be underestimated because the backup ground therapy allowed to be changed throughout the trial, depending on physician judgment. Also, I think the effects of many studies start to look at effects of SGLT-2 inhibitor on out of office blood pressure, like home blood pressure, or 24 blood pressure. Some even that we have published over the years, show more pronounced blood pressure lowering effects when measure outside the office. So I think that it is very interesting study but it could be not just only the drug that we use cardiovascular and renal outcome, but maybe a new class of antihypertensive medication that we could use for that purpose, although it has to be tested. Dr. Greg Hundley: Very nice. Well, Brendan, I want to turn back to you and then we'll come to Wanpen. Brendan, what do you think as a followup study to yours, what do you think is the next study that needs to be performed in this space? Dr. Brendan Neuen: Thanks, Greg. I think there's so much we still need to know about the blood pressure lowering effects of these drugs in people with advanced CKD. It would be very interesting to look at the DAPA-CKD trial, to look at the blood pressure lowering effects in people with advanced CKD not due to diabetes, so nondiabetic kidney disease. These patients also have a high burden of hypertension and whether or not these effects are also present in this population would also be important to know, and study patients with even more advanced kidney disease. That is being done in the EMPA-KIDNEY study with empagliflozin. Those results should be known in the next 12 to 24 months. Dr. Brendan Neuen: So, I'm studying this further in people with kidney disease. And also as Wanpen mentioned, looking at effects on blood pressure phenotype, you know, 24 hour blood pressure dipping status would also be important though, blood pressure variability, all those things can add to our understanding of the effect of these agents on blood pressure. Dr. Greg Hundley: Excellent. And Wanpen, do you have anything to add? Dr. Wanpen Vongpatanasin: Yes. I think one also very important study that helps someone with carrying in the future is in the CREDENCE, the people who are already treated with a mineralocorticoid receptor antagonist were excluded. So whether among resistant hypertension group, adding canagliflozin will be beneficial in those groups already treated MRA and lower cardiovascular outcome in already treated with MRA will be very interesting to see. Dr. Brendan Neuen: Yeah, I think that's a really important point to point out about the design of the CREDENCE trial, that patients who were on MRAs were excluded from the trial initially. This was due to early concerns that canagliflozin might increase the risk of hyperkalemia. I think that risk has now been put to bed in the other SGLT-2 inhibitor trials. We've got more data looking at the effects on serine potassium coming out soon, hopefully, but the other trials in which enroll more patients on MRAs, it will be very important to look at the blood pressure lowering effects in these populations. Dr. Greg Hundley: Excellent. Well, listeners, we've heard a great discussion today and we want to thank Brendan Neuen for bringing this wonderful science to us through circulation at the American Heart Association. We also want to thank our associate editor, Wanpen Vongpatanasin for being present today and helping us discuss how, in patients with type two diabetes and chronic kidney disease, describing that the blood pressure lowering effect of canagliflozin occurs early and appears sustained over the long term and therefore perhaps canagliflozin and can be used or considered as an adjunct blood pressure lowering medicine in addition to perhaps its protective effects on the kidney and other cardiovascular-related issues. Well now listeners, we've got another feature to get onto. So we're going to get to that second feature discussion right now. Dr. Greg Hundley: Well listeners, we are now turning to our second feature discussion and we're so fortunate today to have with us Dr. Saibal Kar from the Los Robles Regional Medical Center in Los Angeles, California, and our own associate editor, Dr. Mark Link from UT Southwestern in Dallas, Texas. Welcome gentlemen. Saibal, let's start with you. Could you describe for us the hypothesis that you wanted to test and what was your study population and your study design? Dr. Saibal Kar: Dr. Hundley, or if I could allow to call you Greg, thank you very much for asking me this question. The hypothesis was that we do know that the WATCHMAN device does prevent ischemic strokes. We do know that the first generation device has a few limitations. So there were some modifications made to the new WATCHMAN device, which is now called the WATCHMAN FLX. We thought that these changes should translate into better safety and better efficacy. So, that was the hypothesis of the study. The study population was patients with nonvalvular atrial fibrillation with a CHADS-VASc score of three or more, who had high risk of bleeding or patients who cannot take long-term anticoagulants. The study design was a single arm, prospective multicenter study with endpoints, which were based on performance goals from previous clinical trials. Dr. Greg Hundley: Excellent. Before we get to your results, Saibal how many patients and how many centers participated in your trial? Dr. Saibal Kar: So as the national principal investigator, I've never seen a study which was enrolled so fast. So the intended population was 400 patients in 29 centers and before half those centers could be activated, the study was over in four months. Dr. Greg Hundley: Congratulations. I think all of us that have ... especially in this pandemic era for recruiting so well, and tell us, what did you find? Dr. Saibal Kar: So what we found is that there were two endpoints, a safety endpoint and the efficacy endpoint. So the first thing that we found is that of the 400 patients, we could actually implant in 395 patients, device actually, which made the primary success rate over 98%. regarding the safety endpoint, we had a safety margin around 4% based on a performance score and set about 2.5, but the actual safety event rate was 0.5%, which was only two minor ischemic events, peri-procedural. There were no pericardial effusions in the first seven days, and there was no device embolizations at any time period, so that was the primary safety endpoint. So we were actually clearly safer than the first-generation device. Dr. Saibal Kar: When it comes to efficacy, it was an anatomical efficacy and we set the primary goal for the previous generation to be 99%. We've made a delta to make it about 97% effective, but we actually achieved an effective closure in 100% of patients. When I say effective closure, I mean that anyone with a peri device leak of less than five millimeters. Going into a little bit of granular detail, we actually found out that 90% of the patients actually had no leak at all. So we did at least achieve both the anatomical as well as the safety endpoints. Dr. Greg Hundley: Excellent. Well, listeners, we're now going to turn to our associate editor, Dr. Mark Link and Mark, I know you have many papers that pass through your hands. What attracted you to this paper. Then, these results really sound significant. Can you describe what impressed you also with the results of this study and how do they relate to other studies pertinent to implantation of devices in patients with atrial fibrillation? Dr. Mark Link: Yeah, we were interested in this paper at CERT because it's the next generation of the WATCHMAN. The numbers of patients that are being implanted with this device to prevent strokes is dramatically going up, but it's not a perfect device. So we were, as the EP community, very interested in the next generation device. We're obviously also interested in other competitors' device, but it's clear that the WATCHMAN is probably the world's leader in this time. So we knew that many of our people reading this magazine, reading the circulation, would want to see how the next generation turned out, was it really safer. That was really the primary goal of this study, it's really a safety study more than an efficacy study because the efficacy was defined by echo criteria, not by clinical criteria of stroke, which is the ultimate criteria. It was a well done study and the results came out more positive than I think even the investigators thought it was going to come out. So we liked it and that's why we did our best to get it published in circulation. Dr. Greg Hundley: Very good. So it sounds like great new innovation and very, very safe, especially relative perhaps to the first-generation device. So Saibal, can you tell us in just a few words, what do you think is the next study to be performed in this space? After you answer, Mark, we'll turn to you and basically ask the same question. Dr. Saibal Kar: Thank you very much, Greg. Transcatheter left atrial appendage closure has been approved by the FDA, specifically the WATCHMAN device, for patients who are candidates for long anticoagulation, but have limitations to long-term anticoagulation and therefore not for all-comers and there's a reason for that. The time has now come to actually evaluate this device for all-comers. That means all patients with nonvalvular atrial fibrillations who are suitable for anticoagulants. Therefore, the next best study is the CHAMPION trial. This study is going to be a randomized trial of the WATCHMAN FLX versus NOACs, or more correctly DOACs, in all-comers, patients with nonvalvular atrial fibrillation who require long-term anticoagulants. It's a 3,000 patients clinical trial with a one-to-one randomization to WATCHMAN FLX or the continuation of DOACs and the primary endpoints will be estimated at three years with a follow-up up to five years. Our goal is to show that we are non-inferior in comparison to stroke and death, and superior respect to long-term bleeding. Dr. Greg Hundley: Very good, and Mark? Dr. Mark Link: Yeah, I agree. The CHAMPION trial is the obvious next trial that everyone wants to see the results of, comparing this device to DOACs. Another trial or data I'd like to see is the immediate post-procedural anticoagulation. It's still an area that we don't have enough data to know how to treat these patients. Traditionally, they've been treated with warfarin and anti-platelet agents, but many of the patients getting this WATCHMAN have a relative contraindication to anticoagulation. So I'd like to see some data on shorter term duration of anticoagulation post-implant. Dr. Greg Hundley: Very good. Well listeners, we've had a wonderful discussion here and we want to thank the lead author, Dr. Saibal Kar and also our own associate editor, Dr. Mark Link, for really providing us with new information that this left atrial appendage closure device met the primary safety outcome in 99.5% of all of those implanted within seven days, what a remarkable finding. So, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.

#456 - NOACs são mais seguros que varfarina em termos de sangramento SNC?

Cardiopapers

Play Episode Listen Later Mar 22, 2021 2:53

#456 - NOACs são mais seguros que varfarina em termos de sangramento SNC? by Cardiopapers

seguros termos snc noacs

Stroke Alert February 2021

Stroke Alert

Play Episode Listen Later Mar 2, 2021 19:39

On Episode 1 of the Stroke Alert podcast, host Dr. Negar Asdaghi highlights two featured articles from the February 2021 issue of Stroke. This episode also features a conversation with Drs. Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, to discuss their article “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.” Dr. Negar Asdaghi: Are women more likely to suffer from stroke than men? Are oral anticoagulants safe in atrial fibrillation patients with a prior history of GI bleeding? Does pregnancy increase the risk of intracerebral hemorrhage in patients with cavernous malformation? Does the number of retrieval attempts during thrombectomy affect the outcomes of stroke patients in whom successful reperfusion is achieved? In today's podcast, we address some of these topics and much more. You're listening to the Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi: From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami, Miller School of Medicine, and the host of the monthly Stroke Alert Podcast. We're starting our podcasts with the February 2021 issue of the journal, which also features a special section on Go Red for Women stroke, a comprehensive American Heart Association platform to improve the vascular health of women globally. I hope you enjoy it. Dr. Negar Asdaghi: Cavernous malformations or cavernomas are angiographically called vascular abnormalities, which can pose an increased risk for intracerebral hemorrhage. Cavernomas can have diverse neurological presentations ranging from mild neurological symptoms to seizures, but in some cases may remain entirely asymptomatic and are diagnosed incidentally as part of routine neuroimaging completed for other reasons. Earlier studies had reported higher rates of intracerebral hemorrhage from cavernomas during pregnancy, and have postulated a hormone-related increased expression of vascular endothelial growth factor or basic fibroblasts growth factors to explain this increased rate. Subsequent studies, however, have failed to demonstrate either progesterone or estrogen receptors in cavernomas. So the question is, should presence of cavernous malformation, whether symptomatic or asymptomatic, influence the reproductive choices of women of childbearing age? In the “Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations,” Dr. Nycole Joseph and colleagues from the Departments of Neurology and Neurosurgery from Mayo Clinic Rochester in Minnesota evaluated 365 pregnancies and 160 women with brain or spinal cord cavernomas. They found that during the cumulative 402 years of study follow-up, the risk of hemorrhage amongst non-pregnant patients in the study was 10.4% per year. They found only four patients with clinical hemorrhage during pregnancy, all of which resulted in the cavernomas being first diagnosed. None of the hemorrhages occurred during delivery, and all of the four patients had functionally independent outcomes by three months. Importantly, they found that no patient who became pregnant after the diagnosis of cavernous malformation had a hemorrhage while pregnant. They had a total of 33 pregnancies in the study, including one patient who had previously bled during a prior pregnancy and also patients with brainstem lesions and those who presented with hemorrhage at diagnosis. Both of these are factors for hemorrhage in cavernomas. So, in summary, in this prospective study, pregnancy did not increase the risk of hemorrhage in women with a known brain or spinal cord cavernous malformation. And the vaginal delivery was safe in this population. The authors concluded that the presence of cavernous malformation should not influence the reproductive choices in women or their type of delivery. Now, speaking of hemorrhage risk, let's move on to our next paper on anticoagulation therapy in patients with atrial fibrillation. The decision to start anticoagulants for atrial fibrillation can often be challenging in those who have suffered from a prior gastrointestinal bleeding. Prior studies have shown that the non–vitamin K antagonist oral anticoagulants, or NOACs, can carry a comparable and, in some cases, even a higher risk of GI bleed than warfarin. It should be noted that patients with a prior GI bleed were generally excluded from the pivotal randomized control trials that approved NOACs. And importantly, the risk of bleeding may also be higher in certain race/ethnic groups, such as the Asian population. In the article titled “Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Gastrointestinal Bleeding,” Dr. Soonil Kwon from the Department of Internal Medicine, Seoul National University Hospital, in Seoul, Republic of Korea, studied over 42,000 anticoagulant–naïve patients with nonvalvular atrial fibrillation and prior GI bleed from 2010 to 2018 as part of a retrospective, observational cohort study in Korea. They evaluated the risk of ischemic stroke, major bleeding and combined outcomes in this population. What they found was that, not surprisingly, close to 60% of patients were initiated on a NOAC, with rivaroxaban leading dabigatran, apixaban, followed by edoxaban in terms of frequency of agents used. Just over 40% of patients were started on warfarin. Now, over the study follow-up, when they looked at the safety by looking at major bleeding rate and effectiveness by assessing ischemic stroke rates, NOACs generally did better as compared to warfarin, resulting in 39% risk reduction in recurrent stroke, 27% risk reduction in major bleeding and 34% risk reduction in composite outcomes as compared to warfarin. And the rates of upper and lower GI bleed were similar in NOACs versus warfarin users. NOACs still did better as compared to warfarin amongst patients who suffered from GI bleed as they had a lower transfusion rates and shorter hospital stay. NOACs were also associated with lower risks of fatal clinical outcomes except for fatal GI bleed. So the authors concluded that contrary to some of the prior reports, NOACs may be a better option than warfarin for stroke patients and atrial fibrillation patients with prior GI bleed. Dr. Negar Asdaghi: Moving from secondary prevention to acute stroke therapy, our last article discusses how the technical details of endovascular thrombectomy may affect the outcomes in patients with ischemic stroke. So, achieving a successful reperfusion is the cornerstone of improving clinical outcomes in patients undergoing endovascular therapy, but how many retrieval attempts should be made by the interventionist to obtain that desired successful reperfusion is still unclear. Importantly, if successful reperfusion is ultimately achieved, it's still not clear if there's a relationship between the number of retrieval attempts and favorable clinical outcomes. Joining me now are doctors Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, who are the first and senior authors of the study titled “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.” Good morning from Florida, and good afternoon, Fabian and Máté, in Germany. Thank you for joining us. Dr. Fabian Flottmann: Thank you very much, Negar, for the nice introduction. Good afternoon from Hamburg. At the moment, it's really, really cold here. It's -4 degrees Celsius. I can't translate it to Fahrenheit, but it's pretty cold, let me assure you. And thank you very much for having us today. Dr. Negar Asdaghi: It's great to have you. So I start with Fabian. This is a very interesting and timely study as we're learning more that the way in which we achieve a goal in acute stroke reperfusion therapies is almost as important as the goal itself. Can you tell us a bit about the background of your study, Fabian, and why you felt the need to look at these granular details, which unfold inside the angio suite during endovascular thrombectomy? Dr. Fabian Flottmann: Of course, that's a question that's highly relevant for a neurointerventionalist. This research topic developed from our clinical practice, because quite often we have the situation in the angiography suite, where we try to open a vessel, a patient with a large vessel occlusion, and everything is very easy if the vessel opens after one retrieval attempt, because everybody is happy and you can end the procedure. But what happens if the vessel doesn't open? Then you try again. And what happens if the vessel doesn't open? You try it again, and so on and so on. So the question is, when should you stop? And we ask ourselves, are these maneuvers that we do, like three or four or five maneuvers, are they as successful or as beneficial for the patient as the first maneuver? We did an analysis of our data in Hamburg, and that led to the first paper that we published in Stroke in 2018. And our finding was that the third or fourth retrieval, they were successful in achieving recanalization, but the clinical outcome of those patients was not as good as those patients that you opened with just one retrieval attempt. That was the first finding that we had with our data and our center. And then in the same year, the first pass effect was described. The first pass effect, being the finding that the first retrieval attempt is the most important for the patient. This data was very interesting. And then there were other publications that said, no, there's no connection between the number of retrieval attempts and the clinical outcome. So, as always, in science, when there's more than one opinion, things begin to get interesting. And we said we want to investigate this further. And we decided to do a multicenter study with more patients. And we decided to look at each retrieval attempt separately, to not look just at a first retrieval attempt versus the others, but at each retrieval attempt. Dr. Negar Asdaghi: So interesting indeed. Please tell us, before you tell us about the study findings, about the German Stroke Registry. How many years has the registry been active, and how many centers are involved, and please walk us through your study population and the selection process of your study? Dr. Fabian Flottmann: Germans Stroke Registry. It's a systematic observational registry study from Germany. It's academic, it's independent, prospective, multi-central, there are 25 centers who participate in this registry. And its goal is to have a systematic evaluation of endovascular stroke treatment in Germany. There are stroke centers from all around the country who consecutively enroll their patients. All patients with an intention to treat in the angiography suite are included. All the patient data are collected at the center and all these data are then centralized and we have a central quality check. And what is important that we also try to include the clinical follow-up information for every patient at day 90. So, the modified Rankin Scale at day 90 is also included. And in our work, we did an analysis of the first 2,600 patients of this German Stroke Registry, and our goal was to eliminate bias. So, for example, we wanted to include data on the stroke severity, the NIHSS score, the amount of early infarction, the ASPECTS score and the location of occlusion, the age of the patient. We selected all the patients that had these data entered. So, we were able to select about 1,200 patients from the German Stroke Registry that fulfilled our inclusion criteria for the present study. To our knowledge, this is the largest multicentric, retrospective study that investigated this effect of retrieval attempts on clinical outcome. Dr. Negar Asdaghi: This is really nice because we are really not used to getting granular details and radiographic details in such large numbers. So, the multicenter nature and the large number of patients included in your study are certainly important strengths of your paper, and that should be noted. Now, Matthew, over to you. Please tell us the main findings of the paper. Dr. Matthew Maros: So, one specialty of our applied methodology is that we used a generalized mixed-effects models, if we didn't know logistic regression framework. That means that our target variable was the mRS90 and the good functional outcome, defined by zero to two scores by mRS. We also implied this framework to be comparable to the HERMES meta-analysis by Goyal et al. And we investigated, in our primary analysis, the effect of age, the baseline stroke severity NIHSS score, ASPECTS score, and also the main explanatory variable that we investigated was the successful reperfusion at N-th retrieval attempt. And we found that, so as one would expect, a younger age and the less severe stroke clinical manifestation, like NIHSS score, was inversely associated with a good functional outcome. So, younger patients and less severe stroke were associated with a favorable outcome. And also, a less severe ischemic changes on a non-contrast head CT, so ASPECTS score eight, nine or ten, were also independent predictors for a good function outcome at 90 days. Our main finding was that the success at the first, second, or third retrieval attempts were significantly and independently associated with a good functional outcome. And interestingly, the effect of the consecutive retrieval attempts were gradually diminishing from an odds ratio from six (around) to three. Dr. Negar Asdaghi: This is interesting. So, basically, what you found is that you go in with the first attempt, second and third, you don't achieve that successful recanalization. If you achieve your successful reperfusion after the third attempt, it's good, but not so good, meaning that it doesn't translate to that beautiful, favorable outcome at 90 days as it did for the first three attempts. Dr. Matthew Maros: So, for four or more retrieval attempts, this positive effect on the outcome has flattened, so the curve is more like a sigmoid curve that was asymptotic to a virtual threshold. Dr. Negar Asdaghi: Understood. So, I find it very interesting that this decline in the odds of favorable outcome, despite successful reperfusion, was not simply a factor of time, meaning that, if you tried once and you achieve reperfusion right away, it's so much faster. And of course, time is brain, but if you try five times, it would take longer. It is interesting in your results and your multivariate analysis that even if you adjusted for the factor of delay in time, the results persisted. Could you please tell us about your multivariate analysis and what other factors and co-founders you adjusted for? Dr. Matthew Maros: Exactly. So, as a sensitivity analysis, we also included the time from groin puncture to flow restoration and also sex, and also to be almost identical or highly similar to the model applied in the HERMES meta-analysis. We also included the site of the intracranial occlusion and better intravenous thrombolysis was administered or not. And in the sensitivity analysis, we had almost 90% of our dataset. So almost a thousand one hundred patients. And we found that all the effects of age and NIHSS score stayed significant, and also the effect of the first, second and third retrieval attempts associated with good functional outcome at 90 days were also significant. While interestingly, the effect of intravenous thrombolysis, and also the ASPECTS score, had diminished, but also just narrowly escaped a significant threshold. And interestingly, the effect of time, so time from groin puncture to flow restoration, seemed to be not relevant or be interpreted that way, that the number of retrieval attempts and the effect that we see is not a surrogate of time, that it simply takes longer to perform the interventions, but it's the true effect of achieving recanalization at a certain attempt. Dr. Negar Asdaghi: So, what should be our takeaway from your study, Fabian? Is three that magic number? Are we asking the interventionalist to stop the procedure after the third retrieval attempt if they're unsuccessful, and what should the future hold in terms of studies on this project? Dr. Fabian Flottmann: That's the most important question. Of course, we have to keep in mind that every patient and every intervention is different. The decision to continue or stop the thrombectomy procedure is a very important decision, which is taken by the neurointerventionalist together with his team. And they will take into account multiple factors, including patient's biography, medical history at time from symptom onset, image data, and so on. Our study can provide some guiding information when making this decision. And yes, three could indeed be called a magic number in the following sense. We would like to encourage interventionalists to make at least three attempts in case of persistent occlusion, because we can see a clear benefit even when reperfusion is achieved after the third attempt. Then, in patients with younger age and/or, for example, a good ASPECTS score, even more retrieval attempts are probably warranted regardless of IV thrombolysis, site of occlusion and potentially increased procedure time. Of course, in all these retrospective studies, a bias remains. We don't know why the procedure was stopped in each case. The best thing would be a randomized controlled trial with the following design. You could, in case of persistent occlusions, after two retrievals, randomize to continue or to stop the procedure. And then we would know what the right answer is. So, taken together, our study suggests that in EVT for anterior circulation strokes, at least three retrieval attempts should be performed in cases of persistent occlusion, and up to five attempts of beneficial association with good clinical outcome is expected. Dr. Negar Asdaghi: Doctors Fabian Flottmann and Matthew Maros, thank you very much for joining us and congratulations on this work. And this concludes our podcast today. Don't forget to check the February table of contents for the full list of publications, including original contributions, brief reports, editorials, and our special section on Go Red for Women stroke. Until our next podcast, stay alert with Stroke Alert.

Natural Blood Thinners for Atrial Fibrillation & Stroke Prevention

Prevmed

Play Episode Listen Later Feb 21, 2021 8:05

There are a lot of blood thinners in the herbal medicine list, like garlic, nattokinase, ginger, cinnamon, cassia, vitamin e, Ginko biloba, grape seed extract, cayenne, aspirin, apple cider vinegar, and cod liver oil. But most of these are antiplatelets, not anticoagulants. Anticoagulants have been shown to be more effective in terms of prevention of strokes. Safety is also an issue. The strokes we're preventing are infarction, embolic, or ischemic strokes. So, we decrease the formation of blood clots. Unfortunately, that also increases the risk for serious bleeding or hemorrhage, such as hemorrhagic strokes. The research has been clear for over 20 years that anticoagulants seem better than antiplatelets for stroke prevention. And most docs will go with the researched recommendations. These days the researched recommendations are leaning more and more toward the NOACs (new oral anticoagulants).For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on stroke & atrial fibrillationPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page

How to Avoid a Wheelchair - Stroke & Atrial Fib

Prevmed

Play Episode Listen Later Feb 14, 2021 18:51

Strokes are the #1 cause of significant long-term disability, the #5 (or #3) cause of death. 55,000 more women have strokes each year. It's decreasing due to better management of blood pressure - the biggest risk factor.But the new challenge in stroke prevention is atrial fibrillation. Paroxysmal (occasional, undiagnosed) atrial fib is becoming recognized as one of the new leading causes of stroke. So, it is becoming far more important to look for atrial fib.Now, it has become clear that there are better ways to prevent a stroke if medication is needed. Aspirin does help. But Plavix is better. Warfarin or Coumadin is even better. But Elliquis, Xarelto, dabigatran--the NOACs (new oral antiCoagulants)--are even far more effective at preventing a stroke.For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on stroke & atrial fibPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page

stroke strokes wheelchairs aspirin atrial warfarin anticoagulants paroxysmal noacs xarelto coumadin

Natural Blood Thinners for Atrial Fibrillation & Stroke Prevention

Prevmed

Play Episode Listen Later Jan 30, 2021 8:06

There are a lot of blood thinners in the herbal medicine list, like garlic, nattokinase, ginger, cinnamon, cassia, vitamin e, Ginko biloba, grape seed extract, cayenne, aspirin, apple cider vinegar, and cod liver oil. But most of these are antiplatelets, not anticoagulants. Anticoagulants have been shown to be more effective in terms of prevention of strokes. Safety is also an issue. The strokes we're preventing are infarction, embolic, or ischemic strokes. So, we decrease the formation of blood clots. Unfortunately, that also increases the risk for serious bleeding or hemorrhage, such as hemorrhagic strokes. The research has been clear for over 20 years that anticoagulants seem better than antiplatelets for stroke prevention. And most docs will go with the researched recommendations. These days the researched recommendations are leaning more and more toward the NOACs (new oral anticoagulants). For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on stroke & atrial fibrillationPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page

blood natural atrial fibrillation stroke prevention anticoagulants ginko noacs

Seeing the Bigger Picture in Cancer-Associated Thrombosis

Play Episode Listen Later Dec 7, 2020 25:55

In this episode, Dr Alok Khorana talks about the evolution of treatment for patients with cancer-associated thrombosis, Dr Ander Cohen discusses the importance of treatment satisfaction in these patients and Dr Jeff Weitz and Dr Jan Beyer-Westendorf discuss the management of a patient with colorectal cancer and incidental pulmonary embolism Further Details: • Data showing the increased risk of VTE recurrence in patients with cancer-associated thrombosis is available here: https://ashpublications.org/blood/article/100/10/3484/106282/Recurrent-venous-thromboembolism-and-bleeding • The dedicated trials on NOACs in cancer-associated thrombosis can be accessed here for edoxaban (https://pubmed.ncbi.nlm.nih.gov/31733403/), rivaroxaban (https://pubmed.ncbi.nlm.nih.gov/31995662/) and apixaban (https://pubmed.ncbi.nlm.nih.gov/28837207/, https://pubmed.ncbi.nlm.nih.gov/32223112/) • More details on the patient reported outcomes in COSIMO can be found here: https://pubmed.ncbi.nlm.nih.gov/32877956/ • COSIMO baseline characteristics and clinical outcomes are described here: https://ashpublications.org/blood/article/134/Supplement_1/2161/427953/Baseline-Characteristics-and-Clinical-Outcomes • The ISTH 2018 guidelines on cancer-associated thrombosis can be found here: https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14219 • The ASCO 2019 guidelines on cancer-associated thrombosis can be found here: https://ascopubs.org/doi/10.1200/JCO.19.01461 • The ITAC 2019 guidelines on cancer-associated thrombosis can be found here: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30336-5/fulltext • The NCCN 2020 guidelines on cancer-associated thrombosis can be found here: https://www.google.com/url?client=internal-element-cse&cx=007894372670309631110:vocdaeamxuy&q=https://www.nccn.org/Common/FileManager.ashx%3FfileManagerId%3Db0461271-ae6f-455a-bbb9-a637326abe49&sa=U&ved=2ahUKEwiTm5-0kcvsAhWNqZ4KHZinDsMQFjAAegQIBhAB&usg=AOvVaw1lR7Ua6h1mBxVItb_BHMe9 • The ESC 2019 guidelines on the diagnosis and management of acute pulmonary embolism can be found here: https://academic.oup.com/eurheartj/article/41/4/543/5556136 • For anticoagulant dosing information, see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf) and low molecular weight heparin (https://www.ema.europa.eu/documents/product-information/inhixa-epar-product-information_en.pdf) (https://www.ema.europa.eu/documents/product-information/arixtra-epar-product-information_en-1.pdf) (https://www.medicines.org.uk/emc/product/4247/smpc#gref) (https://www.medicines.org.uk/emc/product/1695#gref) Recording approval code: PP-M_RIV-ALL-0157-1; Shownotes approval code: PP-M_RIV-ALL-0158-1

european cancer recording gb supplement bigger picture asco recurrent thrombosis cosimo vte jco nccn noacs itac piis1470

Anticoagulation in high risk patients with atrial fibrillation – Episode 3

european management patients recording guidelines esc gb reloaded high risk ruff reload atrial fibrillation european society atrial anticoagulation high risk patients noacs

Play Episode Listen Later Dec 7, 2020 34:43

In this episode, Dr Rónán Collins talks about the links between atrial fibrillation and renal impairment, Dr Hendrik Bonnemeier takes us through the RELOADED study and Dr Manesh Patel and Dr Christian Ruff discuss the management of an patient with atrial fibrillation, diabetes and renal impairment. Further Details: •The 2018 EHRA Practical Guide on the use of NOACs in patients with atrial fibrillation can be found here https://academic.oup.com/eurheartj/article/39/16/1330/4942493 •The meta-analysis of the phase III trials of NOACs by Ruff et al. is available here https://pubmed.ncbi.nlm.nih.gov/24315724/ •Recent presentations of data from RELOADED can be found here (https://esc365.escardio.org/vgn-ext-templating/Congress/ESC-CONGRESS-2019/Poster-Session-5-Atrial-fibrillation-and-oral-anticoagulation-6/199357-comparative-safety-of-factor-xa-inhibitors-vs-phenprocoumon-in-patients-with-non-valvular-atrial-fibrillation-and-renal-disease-insights-from-the-reloaded-study#slide) and here (https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Poster-Session-5-Atrial-fibrillation-and-oral-anticoagulation-1/199283-renal-function-worsening-in-factor-xa-inhibitors-vs-phenprocoumon-in-patients-with-non-valvular-atrial-fibrillation-and-renal-disease-insights-from-the-reloaded-study) and RELOAD is published here (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510975/). •Thrombosis Adviser's coverage of ESC 2019 is here (https://www.thrombosisadviser.com/esc-spaf/) •The 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society Focused Update of the Guideline for the Management of Patients With Atrial Fibrillation is available here https://www.ncbi.nlm.nih.gov/pubmed/3070343 •The European Society of Cardiology Guidelines for the Management of Atrial Fibrillation can be read here https://www.ncbi.nlm.nih.gov/pubmed/16531986 •For anticoagulant dosing information see the European labels for apixaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf), dabigatran (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf), edoxaban (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf), rivaroxaban (https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf) and warfarin (https://www.medicines.org.uk/emc/product/3064/smpc) Recording approval code: PP-XAR-ALL-1963-1; Shownotes approval code: PP-M_RIV-ALL-0127-1

COVID-19 Update: Convalescent Plasma and Tocilizumab | GameChangers

Pharmacy Podcast Network

Play Episode Listen Later Sep 1, 2020 24:00

A recent retrospective study found that patients taking novel oral anticoagulants (NOACs) who were prescribed clarithromycin, compared to azithromycin, had an associated increased risk of major bleeding. This episode dissects the recent JAMA publication discussing the risk of hospitalization among patients taking direct oral anticoagulants and either clarithromycin or azithromycin. https://pubmed.ncbi.nlm.nih.gov/32511684/ This episode is accredited for CPE. For CE details and to claim credit, click here: https://bit.ly/3gvDKKA See omnystudio.com/policies/listener for privacy information.

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Drug Interactions in NOACs: Safer but not completely safe | GameChangers

Pharmacy Podcast Network

Play Episode Listen Later Aug 28, 2020 25:09

A recent retrospective database study found that in patients on new oral anticoagulants prescribed clarithromycin, compared to azithromycin, were assocated with an increased risk of major beeding. We will discuss this paper and other common drug interactions the practicing pharmacists should be vigilant about. This episode is accredited for CPE. For CE details and to claim credit, click here: https://bit.ly/3gvDKKA See omnystudio.com/listener for privacy information. Learn more about your ad choices. Visit megaphone.fm/adchoices

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Drug Interactions in NOACs: Safer but not completely safe | GameChangers

CEimpact Podcast

Play Episode Listen Later Aug 28, 2020 23:54

A recent retrospective database study found that in patients on new oral anticoagulants prescribed clarithromycin, compared to azithromycin, were assocated with an increased risk of major beeding. We will discuss this paper and other common drug interactions the practicing pharmacists should be vigilant about.This episode is accredited for CPE. For CE details and to claim credit, click here: https://bit.ly/3gvDKKA See omnystudio.com/listener for privacy information.

game changers safer continuing education cpe drug interactions pharmacy podcast network noacs ceimpact

Drug Interactions in NOACs: Safer but not completely safe | GameChangers

GameChangers | CEimpact

Play Episode Listen Later Aug 28, 2020 23:54

game changers safer continuing education cpe drug interactions pharmacy podcast network noacs ceimpact

Dr. Baliga's Internal Medicine Podcasts

Play Episode Listen Later Dec 5, 2019 14:40

Preventing Strokes in Atrial Fibrillation -2 2019 ACC/AHA/HRS Update Dr RR Baliga's MUST KNOW FACTs PodCasts for Physicians from Journal of Am Coll Cardiology 2019;74:104-132

journal physicians preventing stroke strokes atrial fibrillation clot atrial warfarin anticoagulants doacs fibrillation acc aha noacs thromboembolism

Dr. Baliga's Internal Medicine Podcasts

Play Episode Listen Later Dec 5, 2019 24:54

Preventing Strokes in Atrial Fibrillation -1 2019 ACC/AHA/HRS Update Dr RR Baliga's MUST KNOW FACTs PodCasts for Physicians from Journal of Am Coll Cardiology 2019;74:104-132

journal physicians preventing stroke strokes atrial fibrillation clot atrial warfarin doacs fibrillation acc aha noacs thromboembolism

Episode 31 – Emergency Department Management of Patients Taking Direct Oral Anticoagulant Agents (Pharmacology CME)

EMplify by EB Medicine

Play Episode Listen Later Aug 6, 2019

Show Notes Jeff: Welcome back to EMplify the podcast corollary to EB Medicine's Emergency medicine Practice. I'm Jeff Nusbaum and I'm back with Nachi Gupta. This month, we are tackling a topic for which the literature continues to rapidly change - we're talking about the ED management of patients taking direct oral anticoagulants or DOACs, previously called novel oral anticoagulants or NOACs. Nachi: Specifically, we'll be focusing on the use of DOACs for the indications of stroke prevention in atrial fibrillation and the treatment and prevention of recurrent venous thromboembolisms. Jeff: This month's article was authored by Dr. Patrick Maher and Dr. Emily Taub of the Icahn School of Medicine at Mount Sinai, and it was peer reviewed by Dr. Dowin Boatright from Yale, Dr. Natalie Kreitzer from the University of Cincinnati, and Dr. Isaac Tawil from the University of New Mexico. Nachi: In their quest to update the last Emergency Medicine Practice issue on this topic which was published in 2013, they reviewed over 200 articles from 2000 to present in addition to 5 systematic reviews in the cochrane database, as well as guidelines from the American Heart Association, European society of cardiology, and the american college of cardiology. Jeff: Thanks to a strong literature base, Dr's Maher and Taub found good quality evidence regarding safety and efficacy of the DOACs in relation to warfarin and the heparin-based anticoagulants. Nachi: But do note that the literature directly comparing the DOACs is far more limited and mostly of poor quality. Show More v Jeff: Fair enough, we'll take what we can get. Nachi: Well, I'm sure more of those studies are still coming. Jeff: Agree. Let's get started with some basics. Not surprisingly, DOACs now account for a similar proportion of office visits for anticoagulant use as warfarin. Nachi: With huge benefits including reduced need for monitoring and a potential for reduced bleeding complications, this certainly isn't surprising. Jeff: Though those benefits are not without challenges - most notably the lack of an effective reversal agent and the risk of unintentional overdose in patients with altered drug metabolism. Nachi: Like all things in medicine, it's about balancing and finding an acceptable risk/benefit profile. Jeff: True. Let's talk pathophysiology for a minute - the control of coagulation in the human body is a balance between hemorrhage and thrombosis, mediated by an extensive number of procoagulant and anticoagulant proteins. Nachi: Before the development of the DOACs, vitamin K antagonists controlled the brunt of the market. As their name suggests, they work by inhibiting the action of vitamin K, and thus reducing the production of clotting factors 2, 7, 9, and 10, and the anticoagulant proteins C and S. Jeff: Unfortunately, these agents have a narrow therapeutic window and many drug-drug interactions, and they require frequent monitoring - making them less desirable to many. Nachi: However, in 2010, the FDA approved the first DOAC, a real game-changer. The DOACs currently on the market work by one of two mechanisms - direct thrombin inhibition or factor Xa inhibition. Jeff: DOACs are currently approved for stroke prevention in nonvalvular afib, treatment of VTE, VTE prophylaxis, and reduction of major cardiovascular events in stable cardiovascular disease. Studies are underway to test their safety and efficacy in arterial and venous thromboembolism, prevention of embolic stroke in afib, ACS, cancer-associated thrombosis, upper extremity DVT, and mesenteric thrombosis. Nachi: Direct thrombin inhibitors like Dabigatran, tradename Pradaxa, was the first FDA approved DOAC. It works by directly inhibiting thrombin, or factor IIa, which is a serine protease that converts soluble fibrinogen into fibrin for clot formation. Jeff: Dabigatran comes in doses of 75 and 150 mg. The dose depends on your renal function, and, with a half-life of 12-15 hours,

university practice european management medicine patients emergency studies cincinnati new mexico fda yale oral mount sinai american heart association maher emergency departments pharmacology acs icahn school taub xa dvt vte doac doacs iia anticoagulant noacs emplify dabigatran pradaxa jeff thanks eb medicine

tmp ep 10 - atrial fibrillation

the medicine podcast

Play Episode Listen Later Jul 10, 2019 18:17

atrial fibrillation afib anticoagulation warfarin palpitations ischemic stroke holiday heart paroxysmal rivaroxaban digoxin noacs apixaban cardioversion metoprolol diltiazem

Circulation March 13, 2018 Issue

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Play Episode Listen Later Mar 12, 2018 17:03

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 Centre and Duke National University of Singapore. Have you ever wondered, which is better for heart health, low calorie vegetarian or a Mediterranean diet? Well, this week's feature paper provides some answers with a very intriguing discussion coming right up after these summaries. The first original paper this week suggests that human fat pools are not the same and in fact are highly diverse in their response to lifestyle interventions during weight reduction first author Dr. Gepner, co-corresponding authors Dr. Shai from Israel and Dr. Stampfer from Boston aim to assess whether distinct lifestyle strategies could differentially affect specific body adipose depos. They performed at 18-month randomized control trial among 278 sedentary adults with abdominal obesity or dyslipidemia in an isolated work place with a monitored, provided lunch. Participants were randomized to an isocaloric low fat or a Mediterranean low carbohydrate diet with or without added moderate physical activity. The overall primary outcome was body fat redistribution and the main specific endpoint was visceral adipose tissue. The authors further followed the dynamics of different fat depos by magnetic resonance imaging. They found that Mediterranean diet was superior to the low fat diet in mobilizing specific ectopic fat depos such as visceral, hepatic, cardiac and pancreatic fats. Exercise had an additional independent contribution to visceral fat loss. Long term persistent moderate weight loss inadequately reflected the significant beneficial effects of diet and exercise on the fat depos. Independent of weight loss, visceral and hepatic fat reduction was mainly associated with improved lipids profile whereas deep subcutaneous fat loss was associated with improved insulin resistance and superficial fat loss was neutral. In other words, two distinct patterns were identified, a differentially responsive depo that was sensitive to the type of intervention, and those recites mostly directly related cardiometabolic health and a uniformly responsive depo, which corresponded only to weight loss per se irrespective of the intervention. Overall, these results suggest that more specific strategies for weight loss may be considered to treat distinct organ specific fat depos in the management of cardiometabolic risk. Current guidelines recommend nonvitamin K antagonist oral anticoagulants or NOACs in patients with nonvalvular atrial fibrillation as these drugs have several benefits over the vitamin K antagonists but do these benefits remain when NOACs have to be combined with aspirin therapy? Well co-first authors Dr. Bennaghmouch and de Veer, corresponding author Dr. ten Berg and colleagues from the Netherlands provided a meta analysis comparing NOACs and Vitamin K antagonists in more than 21700 patients with atrial fibrillation who are treated with concomitant aspirin therapy. NOACs were found to be more effective in terms of stroke or systemic embolism reduction as well as vascular death reduction and as safe as vitamin K antagonist with respect to major bleeding. NOACs were in fact safer with respect to the reduction of intracranial hemorrhage. Thus, these authors found that NOACs were an effective and safe alternative as compared to vitamin K antagonists in atrial fibrillation patients treated with concomitant aspirin therapy. The next study shows that an integrative approach using genomics and proteomics has the potential to identifying new biological pathways for biomarker discovery and pharmacologic targeting in early cardiovascular disease. Co-first authors Dr. Benson and Yang, co-corresponding authors Dr. Wang and Gerszten from Beth Israel Deaconess Medical Center in Boston had recently identified 156 proteins in the human plasma that were each associated with a net Framingham cardiovascular disease risk score using an aptamer-based proteomic platform in the Framingham Heart Study Offspring participants. Now, in the current student these authors hypothesized that performing a genome-wide association study and exome array analyses on the levels of each these 156 proteins may identify genetic determinants of risk associated circulating factors and provide insights into early cardiovascular pathophysiology. Indeed, they discovered dozens of novel genetic variants that were each strongly associated with circulating levels of the Framingham Risk Score associated proteins. They highlighted numerous examples of how these novel gene locus protein associations provided new insights into cardiovascular disease risk pathophysiology including a novel pathway by which the gene phosphatase 1G modulated circulating levels of apolipoprotein E, a key regulator of cholesterol handling. The final study suggests that bariatric surgery represents an effective strategy for reducing antihypertensive drugs in patients with obesity and hypertension. First and corresponding author Dr. Schiavon from Heart Hospital in Sao Paulo, studied 100 patients with obesity and hypertension who were randomized to gastric bypass or medical therapy alone. The patients randomized the gastric bypass were six times more likely to reduce by 30% or more the total number of antihypertensive medications while maintaining controlled blood pressure levels. In addition, 51% of the patients undergoing gastric bypass showed remission of hypertension. Now, the authors are quick to alert that given the morbidity of surgery these results do not imply that all patients with obesity and hypertension should be submitted for bariatric surgery. Rather, these results suggest that gastric bypass surgery represents one extra option to consider in achieving blood pressure control in these patients. That wraps it up for our summaries now for our feature discussion. So, which is better for heart health the vegetarian or the Mediterranean diet? Oh, what an awesome topic and to be able to discuss it from Asia to the United States to Italy, I'm so please to have the first and corresponding author of our feature paper this week Dr. Francesco Sofi from University of Florence in Italy and our dear associate editor Dr. Wendy Post from Johns Hopkins. Francesco, could you please start by telling us what inspired you to do this trial? Dr Francesco Sofi: The aim of the study was to compare two of the most beneficial diets we know from the literature in relation to the occurrence of many chronic degenerative diseases so the Mediterranean diet we have a lot of studies showing that Mediterranean diet is beneficial for many different diseases as well as we have some studies for the beneficial effect of a lacto-ovo vegetarian diet but no studies are available comparing these two diets' dietary profiles. Our hypothesis was to compare in the same population different times the two diets, which were the similar calories, the same isocaloric but just different in terms of composition especially for meat and fish. Dr Carolyn Lam: Tell us the bottom line. I'm holding my breath because I think I've said it before, I'm vegetarian. Half my household is Mediterranean diet so what did you find? Dr Francesco Sofi: We found that in the same group of patients, which were a low risk population because a low risk population here in Italy they were already following a Mediterranean diet but if you control their calories and their composition in terms of the Mediterranean, which included all the different food groups and the lacto-ovo vegetarian diet so all the different groups except for meat and meat-based and fish we noticed that after three months, the lacto-ovo vegetarian diet already determined a reduction of total cholesterol and LDL cholesterol and Mediterranean diet already determined reduction of triglycerides and both were effective for reduction of body weight and fat mass. We noticed with great interest that after three months, all the study population were quite good in [inaudible 00:09:45] with this diet. I mean they didn't have any kind of problems. This is the one of the most important thing and most of the population or many of the patients after the end of the study they started or continued to follow a vegetarian diet. It means that they accepted very well. There was no problem at all. Also, in feasibility and acceptability of this diet and in relation to this also they have a beneficial effect in some parameters such as also oxidative stress parameters and the inflammatory parameters. Dr Carolyn Lam: Right, so if I could summarize maybe crudely so the vegetarian diet, very effective for LDL, the Mediterranean very effective for triglycerides. I know that's a simplification but Wendy, I'd like to know do you think this is the dawn of maybe a more, "Oh, here we go again individualized diet planning"? Dr Wendy Post: I think that this study is really important because there really have been few randomized trials about the vegetarian diet and we've learned a lot of the potential beneficial effects of a Mediterranean diet. I think what was really interesting about this study is seeing that they were both equally effective as a low calorie Mediterranean diet or vegetarian diet at reducing body weight, which is most often the biggest challenge for our patients who are either at risk for cardiovascular disease like these patients potentially were or who have cardiovascular disease. I think the vegetarian diet is potentially an excellent option for some of our patients but it really is an individual choice and I have trouble getting some patients to just give up the red meat let alone any kind of animal meat. I think it really is potentially an individual choice and those who are interested in becoming vegetarian for either health reasons or other reasons these are additional data to suggest potential beneficial effects more to the Mediterranean diet. Dr Francesco Sofi: I think one of the most important things to know from this study is that we have now two options. We need to individualize the diets to patients but if a person wants to follow a vegetarian diet for different reasons including also healthy reasons, we can say that it's beneficial. He or she can follow this diet without no problems so without having any health problems as well as if a person wants to follow also a Mediterranean diet, which included meat and fish with a regular and moderate consumption during the week. Dr Wendy Post: Right but this is just a three month trial with intermediate outcomes so I'm not sure we can necessarily make definitive statements that this is potentially not leading to any adverse effects or some of the other statements that you made. I think we could just make the statements better relative to the outcomes that were seen here related to weight loss and traditional cardiovascular risk factors. Whereas, we have had long term clinical trials of the Mediterranean diet suggesting reduction in risk for events so I think this is definitely supportive of the vegetarian diet but I think we can't say that more studies aren't needed to potentially look at longer term outcomes and more definitive events as opposed to intermediate outcomes that this is a great first start and is really helpful in trying to understand some of the potential differences between the vegetarian diet and the Mediterranean diet. Dr Francesco Sofi: Of course, I completely agree on that. We need more studies and larger studies and longer duration to establish some things but it was just a pilot study but the good thing is the first comparing two beneficial diets. In the literatures now, most of the studies were investigated either already a vegetarian person or vegetarian diet versus a westernized diet so probably there were some biases. Dr Carolyn Lam: Indeed, I want to just echo in these words. Congratulations, Francesco. Beautifully done, very elegant, controlled in terms of caloric intact and I like that message that it's not saying that one is bad and the other is good. It's saying, "They're different but they both resulted in weight loss". I love that comment about getting a bigger study. I want to do it right here in Asia because the diets are just so different here and I'm just wondering how about in the US? Wendy, your perspective? How adoptable are these results? Dr Wendy Post: Well, again I think it's a personal choice and if somebody is willing to become vegetarian then that's potentially wonderful especially if they have high LDL cholesterol and are trying to lose weight but we have to be careful about with the vegetarian diet is the carbohydrate intake, which might affect triglycerides. It might be an individualized approach based on the patient's individual risk factor profile and they're preferences but this is really impressive data suggesting that the vegetarian diet is very similar to the Mediterranean diet in many aspects especially as it relates to weight loss, which is really important. Dr Carolyn Lam: You've hit the nail on the head. Let's remember that this is a low calorie vegetarian diet. I think that's the issue. Sometimes when I say vegetarian diet to some communities here in Asia that is actually a lot of calories and a lot of starch, which is not what we're talking about here. Dr Wendy Post: Right, a low calorie diet so that's the key. That's the hard part isn't it? Dr Carolyn Lam: Yeah, sadly. Francesco? Dr Francesco Sofi: We should say that most diets are similar background I mean in the backbone is similar so a dietary profile full of fruit and vegetables, complex carbohydrates, fiber, so the different things are meat and fish but with you can see in a regular consumption also Mediterranean diet of course, especially Mediterranean diet is beneficial for cardiovascular profile. Dr. Wendy Post: Yeah, if we could get our patients in the United States to follow either the vegetarian or the Mediterranean diet that would be fabulous because they are obviously eating too much in the way of sugar sweetened beverages and deserts and fast food so just trying to follow either of these diets would be especially beneficial if it was a low fat vegetarian or Mediterranean diet. I think we need to get all our patients to be eating more fruits and vegetables, which is a key component of both of these diets and what they share in common, which often can lead to beneficial effects with weight loss due to the increased fiber and satiety and the healthful benefits of high fruit and vegetable diet. Dr Carolyn Lam: Thank you so much. Audience, thanks also for joining us. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Fire Away! Choosing the Right NOAC & How Physician Training Affects Patient Outcomes

The Rounds Table

Play Episode Listen Later Jan 19, 2018 32:47

This week on The Rounds Table we are trying something different as our first new episode of 2018: just the salient points from FOUR articles instead of two! Same time spent listening, twice the take-away! Mike and Kieran break it down for listeners. Novel oral anticoagulants (NOACs) are everywhere, and they can put patients at ... The post Fire Away! Choosing the Right NOAC & How Physician Training Affects Patient Outcomes appeared first on Healthy Debate.

Fire Away! Choosing the Right NOAC & How Physician Training Affects Patient Outcomes

The Rounds Table

Play Episode Listen Later Jan 19, 2018 32:46

This week on The Rounds Table we are trying something different as our first new episode of 2018: just the salient points from FOUR articles instead of two! Same time spent listening, twice the take-away! Mike and Kieran break it down for listeners. Novel oral anticoagulants (NOACs) are everywhere, and they can put patients at ...The post Fire Away! Choosing the Right NOAC & How Physician Training Affects Patient Outcomes appeared first on Healthy Debate.

training patients physicians patient outcomes noac fire away noacs

Circulation January 24, 2017 Issue