Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from The National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today?
Dr Greg Hundley: My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.
As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation.
Dr Carolyn Lam: Interesting, so what did they find, how did they do this?
Dr Greg Hundley: Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription.
Dr Carolyn Lam: And so? What did they find?
Dr Greg Hundley: Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.
So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.
So, Carolyn, how about your next study?
Dr Carolyn Lam: Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial.
Dr Greg Hundley: Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us?
Dr Carolyn Lam: Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.
Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.
So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.
Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension.
Dr Greg Hundley: Wow, so we're getting back toward renal denervation? How about that?
Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.
Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure.
Dr Carolyn Lam: Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes?
Dr Greg Hundley: The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.
The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.
So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy.
Dr Carolyn Lam: Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.
So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz?
Dr Greg Hundley: You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us?
Dr Carolyn Lam: Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.
Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.
So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.
So, Greg, interesting stuff, huh?
Dr Greg Hundley: You bet! Let's go on and here a little bit more about diabetes.
Dr Carolyn Lam: And dapagliflozin coming right up.
Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.
All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please?
Dr Stephen Wiviott: So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.
Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.
And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation.
Dr Carolyn Lam: Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis?
Dr Eri Kato: So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.
So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.
There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.
Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.
So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.
And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.
So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction.
Dr Carolyn Lam: Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined?
Dr Eri Kato: We collected data at the baseline and the heart failure was collected based on the medical record.
Dr Carolyn Lam: So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds?
Dr Darren McGuire: First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.
And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.
So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results?
Dr Carolyn Lam: Subodh, I'm going to let you go first.
Dr Subodh Verma: First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.
I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.
So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.
So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.
But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically.
Dr Carolyn Lam: Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.
But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find?
Dr Stephen Wiviott: I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.
In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.
So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.
And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.
And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.
Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction.
Dr Carolyn Lam: Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next?
Dr Darren McGuire: I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.
And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes.
Dr Carolyn Lam: Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?
You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.
This program is copyright American Heart Association 2019
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss?
Dr Carolyn Lam: Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS.
Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores.
Dr Greg Hundley: Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope?
Dr Carolyn Lam: These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm.
Dr Greg Hundley: Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation.
They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters.
Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges.
Dr Carolyn Lam: Nice, so what did they find Greg?
Dr Greg Hundley: Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term.
Dr Carolyn Lam: Wow, sounds like two really important findings.
Dr Greg Hundley: Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn.
Dr Carolyn Lam: Indeed!
Dr Greg Hundley: Carolyn what about your next paper?
Dr Carolyn Lam: Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial.
Dr Greg Hundley: So, what did they find?
Dr Carolyn Lam: They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that.
Dr Greg Hundley: Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic.
And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan.
Dr Carolyn Lam: Wow, so what did they find?
Dr Greg Hundley: Well did I put you to sleep discussing all of that?
Dr Carolyn Lam: No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources.
Dr Greg Hundley: Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction.
Dr Carolyn Lam: Absolutely!
Dr Greg Hundley: Great.
Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California.
Dr Joseph Wu: Thank you for inviting us.
Dr Nazish Sayed: Thank you.
Dr Greg Hundley: Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results?
Dr Nazish Sayed: So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from.
So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans.
People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes.
But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients.
Dr Greg Hundley: And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed?
Dr Nazish Sayed: In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction.
Dr Greg Hundley: Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon?
Dr Joseph Wu: We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes.
So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use.
Dr Greg Hundley: So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone?
Dr Joseph Wu: I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications.
In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells.
Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful.
Dr Greg Hundley: Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity?
Dr Joseph Wu: This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum.
But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team.
Dr Greg Hundley: Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects.
Dr Joseph Wu: Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies.
Dr Greg Hundley: I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week.
Dr Carolyn Lam: This program is copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first.
Dr Greg Hundley: You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.
This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals.
Dr Carolyn Lam: And what did the study show?
Dr Greg Hundley: So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.
So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.
Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.
What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia.
Dr Carolyn Lam: So how did they show or find this fourth category?
Dr Greg Hundley: Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.
During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.
So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients.
Dr Carolyn Lam: Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are?
Dr Greg Hundley: Aren't cilia on prokaryotes? I mean, I think of bacteria.
Dr Carolyn Lam: All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.
Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling.
Dr Greg Hundley: Carolyn, this is so interesting. I had no idea about these cilia. So what did they find?
Dr Carolyn Lam: So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response.
Dr Greg Hundley: So how do we use this clinically, and what does it mean for us?
Dr Carolyn Lam: These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance.
Dr Greg Hundley: Wow, very interesting!
Dr Carolyn Lam: Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.
So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.
They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases.
Dr Greg Hundley: Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart?
Dr Carolyn Lam: Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.
Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.
So, that wraps up our summaries Greg. Shall we move to our feature discussion?
Dr Greg Hundley: Absolutely.
Dr Greg Hundley: Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.
Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience?
Dr Renato Lopes: The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.
We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.
What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.
So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect.
Dr Greg Hundley: Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race?
Dr Renato Lopes: That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex.
Dr Greg Hundley: Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight?
Dr Renato Lopes: This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.
I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.
It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients.
Dr Greg Hundley: Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation?
Dr Brian Olshansky: It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.
One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.
Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.
We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.
Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight.
Dr Greg Hundley: On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week.
Dr Carolyn Lam This program is Copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, Associate Editor as well, at Circulation, and Director of the Pauley Heart Center in Richmond, Virginia at BCU Health.
Dr Carolyn Lam: Now, we've heard of the PIONEER heart failure trial and that is a sacubitril/valsartan in acute decompensated heart failure. A very important trial, but was powered on the surrogate outcomes. Now, in today's issue though, we're going to hear a little bit more about the clinical outcomes from the PIONEER heart failure trial, a very important paper, a very important discussion coming right up. Greg, what paper do you have to start us off?
Dr Greg Hundley: Carolyn, I've got another favorite of our little discourse, your next Carolyn's Quiz. Except this time it's essay format, so it's open ended questions. And so here's my question to you. What paper addresses an important issue related to hookah inhalation. So Carolyn, do you know a little bit of the origins of hookah and then how does its use compare to e-cigarettes or conventional cigarettes?
Dr Carolyn Lam: Oh, okay. Well at least the quiz wasn't asking if I smoke hookah. Okay, so hookah, that water pipe smoking pipe, fun stuff. I think, is it a Middle Eastern origin? And frankly I don't know of any data to say whether it is better or worse than cigarette smoking.
Dr Greg Hundley: Yeah, you're exactly right. Hookah, it's a longstanding practice, primarily confined to men from the Middle East. But in the 1990s it was introduced with fruit flavored pre-packaged tobacco products and that ignited a sharp uptake of hookah smoking by young women and also men in the Middle East, and then a migration to our western culture. Now, believe it or not, in the United States and in the United Kingdom, hookah has a prevalence of 15% to 25% among university students. And today, twice as many secondary school children smoke hookah as they do cigarettes, and more adults have tried or currently use hookah than electronic cigarettes.
So, what does this article discuss? Well, it focuses on hookah inhalation byproducts, because the charcoal traditionally is used to heat the hookah tobacco in the water pipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products, not only carbon rich nanoparticles and oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide, a putative vasodilator molecule that will dilate the arteries independent of endothelial dysfunction.
So, this study enrolled three groups of patients. First, there were 30 26-year-old hookah smokers. Second, there were 20 in which the flavored hookah tobacco product was heated electrically, not by the charcoal. And then finally, 15 age matched cigarette smokers who smoked one cigarette.
Dr Carolyn Lam: Wow, what was the result?
Dr Greg Hundley: Unfortunately, nicotine levels increased similarly with all types of smoking. Now, flow-mediated arterial dilation, a marker of endothelial function, did not become impaired after smoking charcoal heated hookah, but instead increased by about 43%. In contrast, flow-mediated arterial dilation decreased by 27% after smoking electrically heated hookah, compared to the decrease after cigarettes smoking. For hookah smokers, vasodilation increased 138% times more than in the other two groups. Therefore, the acute endothelial dysfunction was masked by those high levels of carbon monoxide that are generated from the charcoal. Remember, carbon monoxide is a very potent vasodilator.
What do we take away from this, Carolyn? With respect to large artery endothelial function, smoking hookah is not as harmless as discussed by an excellent editorial by Naomi Hamburg from the Whitaker Cardiovascular Institute at Boston University School of Medicine.
Dr Carolyn Lam: Oh wow.
Dr Greg Hundley: You know, importantly, the carbon monoxide is blocking our ability to appreciate endothelial dysfunction with traditional measures. So Carolyn, what about your article?
Dr Carolyn Lam: Going from smoking to exercise, this one looking at intensity of exercise that should be performed after heart transplantation. This is a study from Dr Nytrøen and colleagues from Oslo University Hospital in Norway, and they performed a multicenter prospective randomized controlled trial of 81 patients at a mean of 11 weeks only after a heart transplantation. And these patients were randomized to either nine months of high intensity training, which is a four by four minute intervals at 85% to 95% of peak effort, or to moderate intensity continuous training defined as 60% to 80% of peak effort. And the primary outcome was the effect of high versus moderate intensity exercise on the change in aerobic exercise capacity assessed as VO2 peak.
Dr Greg Hundley: So, what did they find here?
Dr Carolyn Lam: First, it's important to note that it is the first study to test this and to show that the effect of nine months of high intensity training in de novo recipients of heart transplants produced a clinically meaningful, significantly larger increase in peak VO2 and muscular exercise capacity compared to moderate intensity continuous training. Importantly, the study also showed that the approach was safe with high adherence and high completion rates. 96% of patients completed the study, during which time the exercise adherence for both groups was 81% and there were no serious exercise related adverse events.
Dr Greg Hundley: Wow. So it looks like we've been hearing about that in training and athletes. Are there any caveats?
Dr Carolyn Lam: Yeah, and that's an important question. High intensity training in this study required one to one interaction with physical therapists, and of course that's not feasible in most cardiac rehabilitation programs. It also requires motivated, medically stable patients who can maintain high exercise intensity ranges. So further research is really required to determine if these initial improvements at peak VO2 and muscular endurance persist in the long-term period post heart transplantation and, of course, whether they're associated with favorable clinical outcomes. All this is discussed in a beautiful editorial entitled "Can a Hit Result in a Home Run?" by Mark Haykowsky, Wesley Tucker, and Peter Brubaker.
Dr Greg Hundley: Carolyn, that's fantastic. In my next study, I'm going to switch over and discuss diabetes and the age of diagnosis of type two diabetes and its association with cardiovascular mortality and risk findings from the Swedish National Diabetes Registry. The study was conducted between 1998 and 2012 and the analysis cohort comprised 318,083 patients with type two diabetes mellitus matched with just under 1.6 million controls. Participants were followed for total mortality, cardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation.
Dr Carolyn Lam: Huge study. Important question. What did it show?
Dr Greg Hundley: Over a median follow up of about five and a half years, patients with type two diabetes diagnosed under the age of 40 years had the highest excess risk for the most common cardiovascular related outcomes. All risk attenuated progressively with each increasing decade. By the time type two diabetes was diagnosed at an age greater than 80 years, adjusted hazard ratios for cardiovascular disease and non-cardiovascular mortality were all less than one. In addition, survival for those diagnosed beyond 80 years was the same as controls, whereas it was more than a decade less when type two diabetes was diagnosed in adolescence.
Dr Carolyn Lam: Okay, so Greg, what does this mean for us clinically?
Dr Greg Hundley: The observations of this study amplify support for preventing and delaying type two diabetes onset in younger individuals and raises questions as to diagnostic strategies, as to whether we should even screen or implement management strategies for those individuals that are diagnosed with diabetes beyond the age of 80 years.
Dr Carolyn Lam: Interesting. Well, for my last paper, I have a basic science paper and this one really provides insights into endothelial dysfunction. It looks at
S-Adenosylhomocysteine, which is a precursor of homocysteine, and elevated levels of these are positively associated with the risk of cardiovascular disease and with development of atherosclerosis, but its role in endothelial dysfunction has been unclear. So authors Dr Ling from Sun Yat-sen University in Guangzhou, China and Dr Ke from Shenzhen Center of Disease Control and Prevention in Guangzhou, China, these co-corresponding authors and their colleagues performed a series of elegant mouse experiments and showed that the inhibition of S-Adenosylhomocysteine hydrolase resulted in elevated plasma levels of S-Adenosylhomocysteine, which then induced endothelial dysfunction via epigenetic upregulation of the p66Shc-mediated oxidative stress pathway.
Furthermore, plasma S-Adenosylhomocysteine levels were positively associated with oxidative stress levels and inversely associated with flow-mediated dilation and methylation of p66Shc promoters in patients with coronary artery disease and healthy controls. So, this study really provides a novel molecular insight into mechanisms by which this molecule, S-Adenosylhomocysteine, may be associated with endothelial injury and contribute to the development of atherosclerosis. So that brings us to the end of our summaries, Greg. Let's move on to our feature discussion.
Dr Greg Hundley: Welcome everyone to the second half of our presentation where we have an outstanding interview with David Morrow from Brigham and Women's Hospital and Dr Justin Ezekowitz from Edmonton to discuss a letter that we've received, "The clinical outcomes in patients with acute decompensated heart failure randomized to sacubitril/valsartan or enalapril in the PIONEER HF trial. David, can you remind us just a little bit about, first, your New England Journal study, and then how this letter adds to the prior findings?
Dr David Morrow: I think it's first worthwhile to place a little bit of context in that paradigm heart failure trial, which was a preceding trial in patients with chronic heart failure, who were ambulatory patients, who had to be tolerating a stable dose of an ACE inhibitor or an ARB, and could not have had a current acute decompensation of their heart failure, were randomized to sacubitril/valsartan versus enalapril with a significant reduction in major clinical cardiac events with sacubitril/valsartan. And that finding from that trial has led to changes in guidelines and clinical practice for patients with chronic heart failure with reduced ejection fraction.
But there were several important aspects that still left gaps for our clinical care, in that because of a run in period in that trial, so a period where patients had to tolerate sacubitril/valsartan, the stability of the patients that I just described, it often left practitioners in the position of caring for patients who might not meet those inclusion criteria, particularly those patients who are hospitalized where there is an opportunity, often, to update their care to be consistent with current standards and current guidelines. And so we designed the PIONEER heart failure trial with that in mind, to study specifically patients with acute decompensated heart failure, all patients with heart failure with reduced ejection fraction. And they were randomized within hospital initiation after an initial period of stabilization to either sacubitril/valsartan or enalapril in a double blind, double dummy design.
The primary endpoint for the PIONEER heart failure trial was a biomarker, so NT-proBNP, and we saw that there was a significantly greater reduction in
NT-proBNP by four to eight weeks as an average endpoint, by 29% more with the sacubitril/valsartan versus enalapril. And we also saw that the adverse events, the tolerability of the two regimens was similar and the event rates did not differ in the sacubitril/valsartan group.
And so that was the primary result of the trial that was published in the New England Journal of Medicine. We had, in addition, some exploratory clinical end points, one of which was a broad composite which included all-cause mortality, the need for an LVAD implantation, referral for transplantation, heart transplantation, as well as rehospitalization for heart failure. And so, what was new in the letter that we have published in Circulation, is that we specifically looked at the clinical end points and additional exploratory end points, looking at the harder composite of cardiovascular death and rehospitalization for heart failure. And we had particular interest in that because it's being used as a primary end point that was consistent with the paradigm heart failure trial that I described in chronic heart failure. That was really the reason for undertaking this additional analysis.
Dr Greg Hundley: So how did you define rehospitalization for heart failure and what did you find?
Dr David Morrow: Rehospitalization for heart failure, we actually used the same clinical endpoint committee as for the paradigm heart failure trial and used the same definition, which requires that patients had clinical evidence of heart failure, which could include both symptoms as well as biomarker values and evidence of congestion on physical exam. We needed graphic evidence of pulmonary edema. Together, they had to have a clinical presentation that was consistent with heart failure, and then also who have been hospitalized for the management of that decompensation.
And so what we found overall was that there was a significant reduction in cardiovascular death or heart failure with the sacubitril/valsartan over the eight week double blind study period, such that it was a 42% reduction in that end point and an absolute 6% reduction in cardiovascular death or rehospitalization for heart failure with sacubitril/valsartan compared with enalapril.
Dr Greg Hundley: And David, looking at these fantastic figures, for listeners, please take a look at this letter, it looks like the two groups separated early. Can you suggest a mechanism for why that might've occurred?
Dr David Morrow: We agree that it does appear that the separation begins early on. We did not have sufficient statistical power to test individual hypotheses much earlier time points, but the relative risk reduction appears homogeneous over that period. And when we look specifically at 30 days, for example, the relative risk reductions are comparable. So we do think that observation you just made is correct and consistent.
And I think that there's evidence of support for rather early effects on hemodynamic stress. So we have the primary end point with NT-proBNP where we saw that there was separation between the groups that was actually statistically significant on that continuous end point of a natriuretic peptide value already by one week of therapy, which was quite remarkable to us. We had planned as our primary end point the four to eight weeks period where we had expected, based on previous work, that there would likely be a reduction in this slightly different population. But in fact we saw those curves in NT-proBNP separate already by one week. We've also had subsequent work that we presented in abstract form looking at other biomarkers such as troponin and soluble SD2, so biomarkers of wall stress and myocardial injury, and also seeing reductions in those markers that appear also to occur early on.
Dr Carolyn Lam: Justin, can we bring you into this conversation here right now? What do you think are the clinical implications of this particular research letter and then perhaps of PIONEER in general?
Dr Justin Ezekowitz: Thanks Carolyn, and my compliments to Dr Morrow and the team for putting this together as a research letter because that's often a challenge to get to the core information from the study. And I would, again, draw the listeners to get a look at the figures that they put together and especially the way in which they separate early out. And we did ask to be cautious with statistical power about rehospitalization, but it's quite a driving factor for the overall end point and one that shouldn't be lost, because that has the biggest probably clinical implications, that the curves separate early between the groups on an ACE inhibitor versus to sacubitril/valsartan. And given they separate early, one of the clinical implications is, why wait? So why wait for when people have been outside the hospital to change the medication but instead use that as an opportunity when they're in front of you as a clinician to consider switching them over to a newer therapy and consider what they’ve been on from the majority of patients being on an ACE inhibitor or an ARB, but it is the right time when you have them in observation.
The second observation I would make from this study is that although this was done in high quality sites and sites that know how to do clinical research, but also those who take care of patients that are on high quality medications, the baseline medication rate use wasn't perfect. So there's dual opportunity for looking at the baseline medications, which was MRAs and beta blockers, and use it as opportunity and an implication to use all the best medications. And in this case sacubitril/valsartan would be an opportunity.
My final point would be, I think this study is critical from a clinician's perspective, as we've seen many biomarker-based studies where there's a reduction in the biomarker, but the clinical end point doesn't seem to change so NT-proBNP is great, but here is the judicated clinical endpoints. So for me, when I'm treating a patient, that means more to me than the lowering of a biomarker. We've seen other evidence where that doesn't always pan out, and so you are confident now that that is the case.
Dr Carolyn Lam: Well put, Justin. And you had a question, didn't you, for David?
Dr Justin Ezekowitz: Right. One of the questions I was trying to sort through, and we couldn't squeeze this fully into the research letter, was there were some patients who were randomized in the hospital but the overall PIONEER program allowed for up to 10 days, and when you look at the patients and when they were randomized and how they were cared for beginning of the hospital, end of the hostel, right after discharge, was there any difference that you saw across the spectrum of outcome?
Dr David Morrow: Actually, the study drug was initiated in hospital for all patients. We did provide up to 10 days while in hospital for the outer limits of recruitment into this study because we recognized that some hospitalizations for acute decompensated heart failure are quite lengthy, and we wanted to give sites the opportunity to recruit patients who took longer to stabilize in this study than others. So it was starting from 24 hours after hospital presentation up to 10 days as a maximum, but all patients were initiated in hospital.
The median turned out to be at 68 hours and at least three-quarters of patients were recruited and randomized within 98 hours. So the vast majority were early on. Overall, when we look at the consistency of the effects of the primary end points of the natriuretic peptide and a broader composite, we did not see any evidence of heterogeneity based on the timing of randomization relative to presentation. As you pointed out earlier, we have to recognize that the numbers do get smaller across that tier, particularly when we get out to the later window. Still. I would say that the primary results, almost in any trial you should always go by the primary result, and we did not see any heterogeneity to think that there was a different effect in those who were enrolled early or late.
Dr Carolyn Lam: David, can I just chime in and say again, congratulations on this great work. Can I go back to one of the points that Justin made a bit earlier? This being a research letter, could you maybe share with the audience a bit, what's it like to write and be constrained to such few words and a single figure?
Dr David Morrow: Well, as Dr Ezekowitz said, it does present a little bit of a challenge. You have to be very concise. We certainly were fortunate that we could leverage the primary publication for the majority of methods and other design elements that we didn't need to recapitulate. And so I think for, in particular, this type of research where there was something that we felt was quite important scientifically with potentially important clinical implications, but yet still was an additional exploratory end point that we could express concisely, the research letter was a very reasonable format to do that.
Dr Carolyn Lam: I couldn't agree more. But Justin, how about from the editor's point of view? Could you share about the research letter?
Dr Justin Ezekowitz: My compliments to Dr Morrow and his team, as I asked him a lot of questions that required both expanding on the things they had to say while constricting the number of words at the same time, and that's a huge challenge to get findings across. So they were able to meet that challenge. I think one of the key things was really honing down as to what the key messages are, as Dr Morrow just alluded to, you can refer to the main complication or a baseline trial publication for all the other details, but what were the core things that could be demonstrated in a publication that is of a limited number of words, tables, or figures. And I think that's the key is, what is the real hypothesis and question to be answered. And that's the way we focused on all the efforts. I did appreciate that it was not easy not to have a lengthy discussion. So we had a ... in the written discussion we have really just truncated this down to a few key sentences which summarize the overall study, so the reader could pick this up and know what the implications are without actually having to go into a lot of the detail that we've just been speaking about.
Dr Carolyn Lam: Ah, I love it. And thank you so much for this conversation too. That helps us go under the hood a little bit. I'm sure everyone who's listening just wants to pick this up now because it's so concise, so beautiful to read, and just look at the figure.
Thank you everyone for joining us today. Don't forget to tune in again next week to Circulation on the Run.
This program is copyright American Heart Association 2019.