Stephen J. Greene, MD, Assistant Professor at Duke University School of Medicine reviews new treatment options and the role they plan in treating heart failure.
Great. Well no, thank you very much for that kind introduction and also the kind invitation. Very happy to be here. I'll let you go ahead and get started. I'm gonna drop off and then we'll we'll we'll connect again towards the end for Q. And a session. Perfect. Thanks very much so. Um title to talk today is a guideline directed therapy for heart failure in the United States. Where do we stand and where can we go? These are my disclosures. So this is the outline that I'd like to share with you this morning. And it really the first thing we'll talk about is the underlying evidence for the use and dozing of the guideline directed medical therapies that you're all familiar with. Will then discuss the current gaps in GMT, particularly in the United States. But then we'll go to well, how do we know we can actually do better, How do we know we can close those gaps or is it futile. And then lastly the good last bit of the talk will be on discussing ways for the future potential strategies for improving in closing these gaps. So let's jump in with underlying use and dozing evidence. So to place you know, we're all very familiar with the advances in medical therapy that we've made for heart failure with reduced ejection fraction, particularly of late but to place these advances in context, I think it's helpful to consider what the natural history of heart failure is without any disease modifying therapy at all And to do that. You know one way to do it is to go back all the way to 1991. When you consider the solve trial with an alibi real really our first one of our first trials for a disease modifying therapy for hef ref. And at the time, you know, standard of care was really just diuretics and digoxin. And when you look at the placebo arm in the solve trial, just getting directs into Jackson, you really get a sense of the natural history of this condition And over about 3.5 months of follow up, you had exceedingly high mortality of 40% And you had rates of mortality in heart failure, hospitalization of 57%. Remember these are not necessarily advanced people that we would think of as advanced heart failure. This is an outpatient trial. Um you know, and still extremely high mortality rates on the background of the Jackson and diuretics. But as you're all familiar, we've now made major advances and we now have multiple therapies prove it in large randomized clinical trials to improve clinical outcomes, lower mortality, reduce heart failure, hospitalization, improve quality of life. But while we're all familiar with these therapies, we know they work. It's also important to understand. Well, just the magnitude of benefit that we're talking about. It's not just that these work is that they have substantial large benefits. We're talking about reducing all cause mortality really the highest bar end point that we're talking about in a trial of any kind. And we're talking about numbers needed to treat to prevent one death over five years of less than 20 for all these therapies. But also just consider the relative risk reduction that you see with these therapies. When you look at triple therapy and we do network meta analyses um to analyze this, you look at our any beta blocker and mara projected to have a 63% relative reduction in mortality compared with placebo. And now when we have state of the art quadruple therapy, adding SGL T two inhibitor to the mix. Now we're talking about a 74% relative reduction in mortality. So truly major advance from the solve trial era but guidelines don't just say we should use these therapies. They say we need to titrate them to the maximum tolerated or target dose. But why should we care about dose? Well, simply put one reason we need to care about doses because these are the doses that were shown to be beneficial in the randomized landmark clinical trials. And these were the protocols entailed. So when you're looking at these protocols, they all followed except with SGL T two inhibitors which is really one dose. But for the more historic trials, you know, they followed gradual protocol limited. Uptight tray, shin tolerance limit. Excuse me, gradual tolerance, limited up filtration every couple weeks until the target dose of these medications were achieved. Lower doses were prescribed only when the target dose cannot be achieved. And you know, using these gradual tolerance limited protocols, The majority of patients in general did reach the target dose but also just to place the column in the pink in further context, you know, important to realize that not everyone in the placebo arm achieved target doses of placebo. So there is some effect of deciphering what's medication effect versus heart failure itself. And in true intolerable city to a medication. So for example, in merit HF, You know the beta blocker arm, 64% achieved target doses of October law But only 82% achieved target doses of placebo. So again, I think makes these numbers about reaching target even more impressive. But even as further context, we need to recognize that not only is that what the trials did in looking at the protocols, but just taking a step back every trial that has reduced mortality has aimed Whether they got there or not, they aimed to achieve the currently recommended target dose. No trial was, let's start five mg of the center rail and just leave it be and not try to uptight. Trade it all these trials that reduce mortality that we site, they all try gradual tolerance, limited up titrate in every couple of weeks. But not only was that what that was done in the trials. Looking at those protocols, we also know that higher doses beneficial because we've done dedicated our cts of low dose versus high dose. This is one example here the atlas trial randomized patients to low doses centerville versus high dose. This center over a median follow up of almost four years. And you see with high dose the center pole compared to low dose 10% incremental relative risk reduction for cv mortality, 15% proceeding mortality. Heart failure, hospitalization, 24% for heart failure, hospitalization. And importantly in this blinded randomized controlled trial, no difference in drug discontinuation between the groups. Same thing has been seen in the trial of beta blocker therapy, the mocha trial, forearm randomized trial, higher dose, medium dose, low dose carvedilol versus placebo. And you see here nicely on the figure there was a dose dependent improvement in both ejection fraction and six month mortality with higher doses of carbon to law. And again across all four arms, no difference in drug discontinuation of carvedilol arms against placebo. So in summary we already, most, most people we all know about the use of these medicines but just to drive home the point about dozing, we need to care about dozing. I think for one because that's what we did in the landmark clinical trials that reduced mortality. If you're trying to generalize that to your practice, we should try to emulate what they did in the trials. And importantly recognizing that every trial with exception of SGL T two inhibitors, which is really one dose not as relevant, but every trial that reduced mortality aimed whether they got there or not, they were actively aiming to get to the target dose and then also recognizing that dedicate our cts of ace inhibitor, Air B and beta blocker. Have shown incremental benefits with higher doses of those medications compared with lower dose. So we just discussed some of the very strong evidence for the use endorsing of these G. D. M. T. S. Well, how are we doing in contemporary US practice? And to address this question, we designed the champ HF registry which is a prospective observational, non interventional registry of adult out patients with chronic frf less than equal to 40%. Um Across the United States Patients were enrolled in these outpatient practices between December 2015 Through October 2017. Um in this paper here presented the data for baseline data for the 1st 3500 or so patients across 150 us sites including both primary care cardiology and heart failure clinics. So, you know, while we're all we're expecting to see some gaps, I think the magnitude of these gaps really came um really stood out and really um you know, I think they speak for themselves, you know, looking at the percent among patients that are eligible for these therapies in the United States, you know, more than one in four patients eligible are not receiving an Ace harbor Arnie one in three were not receiving a beta blocker in two and three eligible for an Mra were not receiving it. And then even more sobering when you kind of, when you layer these therapies together and ask yourself what about Triple therapy? What about the proportion of patients eligible for these therapies that are getting all three classes, less than one in four patients eligible to receive Triple therapy were actually receiving it at any dosage, but not only were there significant gaps in the use of these medications. We also saw that when these medications were prescribed, they were generally prescribed at low or sub target doses. You see the pie charts displayed here and you see that blue is the target dose Um and getting for the majority of therapies we see less than 50%, target Or kind of that 50%, area range. And then when you layer it altogether asking yourself well the ideal is to be on at the time of Champ. Was to be on target doses of triple therapy, how many patients is that is that hit? Only 1% received triple therapy at the Target Doses in the Champ Registry. So, but even more sobering is that when you compare the data from champ to data from almost a decade ago, improve HF which was another outpatient heart failure registry in the United States, you see that despite intervening strong guideline recommendations, clinical trial evidence, quality improvement initiatives that have been tried over and over again. Professional society initiatives. We really haven't made much progress at all and they're still remain very similar gaps compared what we saw nearly a decade ago and he's very foundational therapies, disease modifying therapies for hef ref. So then as a secondary question, the initial data showed you was a cross section essentially. Just one point in time. What is the use endorsing of medical therapy? Well a secondary question we have. Well what happens if you follow the same group of patients over time in their heart failure journey? What happens to their titillation of medical therapy? What happens to that? True? They say optimize G. D. M. T commonly used in notes. What is really happening during longitudinal follow up And this is what we observe when we compare the dose 12 months later with what the doses and use of these therapies were at baseline. See that among patients that were eligible for all therapies over the one year of outpatient follow up repeated clinic visits, most remain on low doses or received no medications at all. Despite again, long term one year follow up and then when you break it down in three month intervals essentially. Again, looking at more granular detail, you know, portion of patients on no medication, low dose, high dose et cetera. You see these kind of horizontal bands of color suggesting that there is very minimal change in G. D. M. T across at each three month interval very few medication changes over time. The vast majority of patients remain on sub target doses are no dose at all. Um And again it really begs the question of a strong culture of clinical inertia and this idea of set it and forget it where we seem to make an initial decision on a medication and then let it ride. But while these data are very sobering um now the next obvious question as well, can we improve upon this? Can we actually do better in the United States? And I've showed you so far this morning that well on one hand we have the high rates of use and dozing of G. D. M. T. And the randomized clinical trials. But now on the other hand I prevent I present the very low rates of use and dozing and US practice, you know the nihilist um and approach to this as well. Well steve this is different because patients in clinical trials they don't represent real world practice. You know they call it the test tube argument thinking that clinical trial evidence may not generalize to the patient that I'm seeing in front of me in clinic. Those patients in the trial are not real world, so to speak. But I think there is pretty overwhelming evidence that we can do indeed much better. And while I will acknowledge that there is always going to be some persistent differences between patients who consent to be part of a randomized clinical trial and the patients in quote unquote real world. Us practice is always going to be some element of a persistent difference, I think it's clear that the sheer magnitude of the gaps that we are seeing suggests suboptimal quality of care and clinical inertia towards medication changes for GMT. But aside from looking at the sheer magnitude of gaps, how do we know based what are lines of evidence that tell us that we can indeed do better. I'm going to go through quickly what I think are five lines of evidence that make it clear that we can indeed do much better and it's not just futile because these are real world versus clinical trial patients that we're comparing. So the first line of evidence suggesting that we can do much better is that again, although there are some persistent differences between trial patients and clinical practice patients, those differences might actually be smaller than we think this was an analysis comparing paradigm HF the patient population in that trial, which was the landmark trial that gave us to cuba travel certain versus champ HF. Us clinical practice outpatients and what we saw was that, you know, they're very similar overall baseline characteristics between these two cohorts in terms of age blood pressure. Ny class ejection fraction again, differences were not as large as we might have thought and also when you look at their their magic risk score for mortality, essentially looking at what their how how high risk these patients were again, very similar between the clinical trial patients and paradigm and clinical practice in champ HF. But despite this similar clinical profile. Despite a profile that would suggest that patients in champ would be able to tolerate. And also benefit for the most part from security level. Sarin. Only 13% of eligible patients in Championship were prescribed controllable starting at baseline. So appear it appears to be a major gap in the use of that disease modifying therapy. But moving on now, line of evidence, number two, suggesting we can do much better is simply put other countries do a better job than us. And this is an example here comparing the check HF registry from the Netherlands with champ HF from the United States and compared with the U. S. The Netherlands patients had similar blood pressure, similar N. Y. H. A. Class. They actually tended to be older and they actually tended to have modestly worse renal function pair with the U. S. Patients. But despite that they received much more G. D. M. T. Than patients in the United States. And these are not necessarily. The newer therapies are generic. ASR beta blocker camera therapies cost should not be an issue. But again look smaller gaps in the Netherlands compared with the United States. Point # three is that it's important to recognize that large gaps exist even among patients with, you know quote unquote blood pressure room. So you know, we're concerns about hypotension causing low blood pressure and side effects with G. D. M. T. Are commonly cited as a reason why patients don't get uptight traded or there's hesitancy to start a new medication. But when you just look at the objective data Among patients with a blood pressure systolic greater than 110 or less than 110 in champ HF. There was no difference in the gaps in these foundational medical therapy suggest suggesting that although we talk about blood pressure a lot seems to be data say it's less about actual actually the blood pressure and seems to suggest more of a quality of care clinical inertia issue at play Point #4 was already mentioned. Um but you know suggesting that we can do much better to simply simple put simply put we don't make medication changes when we follow patients over one year follow up but set it and forget it approach that I spoke about before and you know really asked we have to ask ourselves when we look at these data. You know are all this magnitude of patients are they all truly at the maximum tolerated dose. They're all they're mostly at some target but is it truly maximally tolerated at each and every clinic visit? I think it's much more likely that you see the magnitude of gaps and it suggests that we're more likely falling asleep at the wheel then actively getting our patients to the true maximum tolerated dose and then point number five why I think we can do much better is also simply put some practices in the United States do this very well and others not so well. And this suggests that this kind of practice level variability suggests that true improvement on a national scale should be possible. You know when we looked at it in Champion Chef We defined opportunities achieved as prescribing a med to an eligible patient at least 50% of target dosage. You know, some senators achieved as many as 70% of all their opportunities with their patient population whereas others achieved only about 10%. So while there surely is some difference in patient population between different practices, this magnitude of variation again suggests that overall we can do much better as a system. So now let's discuss some potential strategies for improvement and you know this list that I have on this summary slide is meant by no means to be exhaustive. Um but I do think these are four that I wanted to highlight that. I think potentially have maybe the highest yield. Um and the first one will be talking about targeting patient awareness, patient education of GMT. So um the data on this slide, we're really very interesting study that I was proud to collaborate on. It started as a focus group session with Duke heart failure patients where we had them here to help design a survey to try to get the patient perception on their condition and also what they thought about therapy and prognosis and using the information we collected in these focus groups. We then made a survey and distributed it to a nationally representative sample of us heart failure patients and I think that you know, I use the word sobering a lot to describe a lot of the data that we've seen so far. But this is again, no exception. Really humbling data that when you look at a very simple question, you're asking patients in the United States with heart failure, do you recognize these therapies? Are you familiar with them? Have you heard of them? You know, while we saw that 75 to 85% of patients were familiar with beta blockers? Diuretics srv as treatment for heart failure, so not perfect, but pretty good. But then on the other hand, you know, two of our four pillars of G. D. M. T. Arnie and mara therapy, one a newer therapy and one of therapy that's been around for some time. More than three out of every four of these patients had not heard of these therapies proven to make them live longer and feel better based on clinical trial evidence and guideline recommendations, but also sobering is that even when patients had heard of these medications, even when they were familiar with these medications, despite the strong evidence for efficacy and safety that we all site at academic conferences and the guidelines talk about, you know, when you ask patients 25-45% of us heart failure patients who had heard of these therapies did have concerns over either the safety or effectiveness of G. D. M. T. I think this kind of brings home in the covid era where we Talk about trust in science and communicating that to our patients. But again, um you know, again very almost half some therapies, 45% again question the safety and effectiveness of these therapies that are really foundational to their heart failure care. Well that describes the gaps in patient education and patient awareness with GMT but is this actually a target for intervention? If we modify that education piece, can we actually improved G. D. M. T. Well, I think really a nice example testing this hypothesis was the epic HF trial which was presented um last year at H. A. By Larry Allen and colleagues from Colorado. And they asked a very simple question can activating quote unquote patients prior to a clinic appointment lead to better engagement with their clinician at that visit around there. Hef ref medication plan and will in turn that better engagement lead to actual better optimization and GMT. And the short answer is that it was a positive trial and that their intervention which was a three minute patient activation video in a one page medication checklist that was sent to patients upstream of their upcoming clinic visit. That did seem to prompt them communicating with their provider. They're nudging their clinician and it led to more GMT intensification. 49% of the patients getting intervention had GMT intensification at that clinic visit, whereas only 30% had had an intensification with usual care. So again, while I think this needs to be scaled and thought about other health systems outside of Colorado certainly is very encouraging that patient education is modifiable and potentially a means to improving GMT utilization. But a second strategy that will now discuss is um you know, again I think very powerful and something that we can actually do today in our clinical practice don't necessarily need more data in my opinion. But that is the idea of heart failure hospitalization as an opportunity and the idea of in hospital initiation of G. D. M. T. So I think we need to think every heart failure, hospitalization is not just a diaries and discharge affair. Um you know, we need while symptoms of congestion are the primary reason that patients report. And you know, there's an initial focus on giving ivy Lasix and you know, trying to make sure they are feeling better quickly. You know, we also need to understand that these are opportunities these hospitalizations that there are risks associated with failure to improve and optimize GMT during that heart failure hospitalization and one of those risks of not optimizing therapy, not initiating therapy for which patients are eligible is that unfortunately the data from us clinical practice show time and time out that differed in hospital initiation unfortunately equals never initiation or a substantial delay. You see here data for three of the four pillars for G. D. M. T. I suspect the findings are going to be the same for SCL T two inhibitors unfortunately. But when you have a patient that's eligible for therapy, what you do in terms of prescribing that therapy a discharge or choosing not to describe prescribe that therapy a discharge matters for how they're going to get that therapy post discharge for looking at beta blocker therapy, Deferring, deferring prescription at time of discharge equals a 70% chance that patients not going to get a beta blocker prescription in 60 90 days post discharge. Looking at our knee and camera for Arnie not prescribing Arnie had discharged the eligible patients, 93% chance they will not fill a prescription in the next one year for that Compared with 80% if you do prescribed at discharge. Same thing. Same concept for camera over 33 out of four patients if you defer and say let's let the outpatient provider take care of it. More than three out of four will not fill a prescription for Mara. So I think while there's sometimes concerns so I don't want to step on the outpatient providers toes. I don't it's not my business to modify their chronic out patient G. D. M. T. I think the data, you know while there's well intentioned to defer the outpatient doc people. We mean, well we cannot assume that outpatient clinicians will start appropriate therapy and that we need to recognize the power of in hospital initiation in hospital initiation almost takes advantage of that clinical inertia that I talked about before. You know, there's very few medication discontinuation once patients already on therapy. So really take advantage of that set it and forget it approach, so to speak, get patients on therapy at discharge and for the most part it's going to persist into longer term use but it's not just about use of these therapies. You know, it's also about this the hard clinical outcomes and that the risk of not optimizing G. D. M. T. In hospital is that the early post discharge risk of CB death in heart failure hospitalization. This is a prime example with Arnie and the Pioneer HF. Trial. This is a trial of patients hospitalized for heart failure randomized to an al april versus switching to Arnie. And in this clinical trial at just eight weeks you see very rapid separation of event curves at eight weeks, you see a 6% absolute risk reduction for CB death. Heart failure hospitalization, 42% relative risk reduction. So you know, if we defer to the outpatient setting weight, even a few weeks it comes as an opportunity cost exposing that patient to excess risk of CV death in early 30 day readmission which were all obviously very sensitive to. So again the risks of not in hospital initiating these therapies risk that they'll never get started to begin with, but also the risk of hard clinical outcomes being much worse. Third potential strategy that will discuss is the idea of medication titrate in clinics and pathways. So we discussed that the goal in the recommendations from the guidelines are to initiate these therapies but also to titrate them to the maximum tolerated or target dose. And when you look at the expert consensus recommendations, they recommend generally speaking to do this every two weeks um and until the target doses or maximum tolerate or achieve and they talk about monitoring heart rate, blood pressure, signs of congestion etcetera. And while they don't necessarily say this has to be an in person visit, I think if you read this you might think that you might be hard pressed to or obligated to have this be done as an in person visit. But then you also say that well having patients in your clinic every two weeks is oftentimes logistical challenge for both patients and providers and that routine practice many of our stable hef ref patient just based on the constraints on our clinic schedules and travel, you might not come maybe three every sick, maybe every three months every six months, maybe even out to a year. Um You know when they when they check in um So every two weeks to do this kind of grab this up filtration could be difficult. Well what about doing virtual remote algorithm based filtration. And I think in the covid era this has become even more into focus. And one of the nicest examples of this potential strategy action was from the Brigham group led by Dr Desai and this was a what's called a navigator led approach is what they called it. And the primary interface with patients were pharmacists. And these navigators, navigators were generally people with bachelor's or master's level degrees without necessarily any clinical training but operating in conjunction with pharmacists and under the supervision of a clinician. And what these navigators did was just follow an algorithm. Very strict algorithm based approach over the phone and patients had home blood pressure cuffs. The navigators and the pharmacist ordered lab checks. They need to come in for an in person assessment. Just go get your blood drawn and we'll follow up the results And over 140 day mean follow up this resulted in almost nine calls on average to the patients and resulted in about four medication changes per patient. And this was an observational study. So not randomized but we needed to have that in context. But I think the data for the patients that were operating under the remote gMT optimization versus usual care are striking when you look at the remote GMT optimization. Following this algorithm based navigator led approach, we saw that there was statistically significant improvement in S. R barney use And beta blocker use at three months follow up in a trend for higher use of camera whereas you're looking in usual care and the usual care included patients following with heart failure. Doctors and cardiologists in the Brigham system really flat line no change, no hint of a change in the quality of GMT in the usual care arm. So again suggests that maybe and also I didn't show it on the slide from an adverse effect profile and hospitalization issue essentially. No no difference for the most part. Um So again really suggests that this remote idea of remote GMT optimization can be a useful tool for our therapy for getting our patients on therapies and tight trading the maximum tolerated dose. I talked earlier, the champ HF data suggest is set it and forget it. This might be one way to break that culture of um and having algorithm based approaches. Maybe we're the clinicians a few steps removed, maybe not having the clinicians overthink things. Follow the algorithm. Maybe it'll move the needle with our G. D. M. T. U. S. So last strategy that I want to discuss is the idea of simultaneous or rapid sequence initiation in the sense of urgency with hef ref medical therapy and you know while all these four strategies we have the patient awareness and the medication titillation clinic, those two pieces, you know those are going to need infrastructure and you know things that you might not be able to do exactly today in your usual practice. But I think the simultaneous or rapid sequence initiation. I really think this is worthy of consideration along with in hospital initiation as things that we can actually do today to improve gmT us for our patients. So to explain rapid sequence in simultaneous initiation of G. D. M. T. Let's first consider the status quo approach. You know we talked about with champ HF show, we talked about the set it and forget it but really just to go over the status quo, the status quo has really been a serial and selective approach to optimizing Gmt. You have a patient that's been diagnosed with Hef ref you sent you might spend the first few weeks and months getting them on an ace inhibitor and a beta blocker or titrate up the dose somewhat, making sure they're tolerating thing, tolerate everything. Okay after a few months you then start an M. R. A. You titrate that up and sure tolerable itty. Then after the cameras on board then you say okay well let's switch now from an Ace inhibitor to Arnie, make sure that's tolerated okay And then lastly then you say okay now it's time to start the SQL T two inhibitor. Okay now they're now they're on quad therapy. Well that trip to quad therapy um could potentially take despite the best intentions despite the most close rigorous follow up can take 28-56 weeks potentially before G. D. M. T. is fully implemented at the true maximally tolerated or target doses in each step. You risk clinical inertia, you risk a missed clinic visit, you risk a heart failure, hospitalization, you risk any of those things getting in the way of this long and somewhat circuitous pathway to maximally tolerated target dose quad therapy. So what I am proposing is what I call simultaneous or rapid sequence initiation of quadruple medical therapy for hef Ra. And the key concept here is to start all four mortality reducing drugs without delay on day one or in rapid sequence within a few days of each other or maximum within one week of each other. And this would apply to both in patients or out patients. And for notably for Arnie beta blocker and Emre we would initiate low doses of these therapies at first and then titrate them up over the subsequent days to weeks. Okay well sounds nice but what is the rationale for simultaneous or rapid sequence initiation? Well the first part of the rationale is simply put the clinical benefits of each of the quadruple medical therapies don't take months or years to show up. But the clinical benefits of each of these four therapies appear within days to weeks. Following G. D. M. T initiation there is a rapid separation of event curves. Um And these are for hard clinical endpoints again within days to weeks of starting. So then it makes it clear that delayed initiation of any of these. Four of these four drugs in an eligible patient unfortunately equals needless exposure to access clinical risk. And the latest example we have with this is with SQL T two inhibitors. And the slide here I think nicely presents that this is not for a surrogate endpoint like Nt pro BNP reduction or a biomarker of of any sort. It's about hard clinical events risk of death, heart failure, hospitalization, urgent heart failure, visit at just 12 days Following initiation of an Sette two inhibitor. We see a 58% relative risk reduction for this hard clinical endpoint that achieves statistical significance. And when you see when you we all know that heart failure is a very high risk condition. But considering some of our pages are exceedingly high risk, like even think of our average garden variety patient hospitalized for worsening half raft. One in four of those patients hospitals for hef ref is dead or re hospitalized within 30 days of discharge. Do we really have time to wait and withhold a therapy proven to decrease risk of those clinical events? The answer is clearly not. But aside from the early clinical benefit, it's also important to recognize that simultaneous and upfront use of these therapies in short order may actually enable tolerance of the full quadruple medical therapy regimen and take for example, as she L. T two inhibitors decrease risk of hyper colonia, slow progression of renal dysfunction. Likewise, to cuba travel sarin compared with an ace inhibitor decreases risk of hyper colonia uh with an Mra. But these effects don't just equate to benefits on lab values like potassium or G fr on your basic metabolic panel every morning. But they actually equate to less mra discontinuation. Data on the left. Remember reduced show that in Pagan flows and reduce the risk of mra discontinuation by 22%. Likewise, in paradigm HF to cuba travel starting compared with an alibi will decrease the risk of mra discontinuation. So I will argue that delaying initiation of an SG LT two inhibitor or delaying a switch from ace inhibitor to Arnie in an otherwise eligible patient needlessly exposes the patient excess risk of developing hyperglycemia and excess risk of emre discontinuation. The goal is need not delay with these therapies. But of course, you know I'm proposing simultaneously rapid sequence initiation. Of course there will be criticism of this approach. There will be hesitation and one of the common criticisms I receive is, well, won't starting multiple medications that once increased risk of intolerance. Um how would you know, if there's a problem with if there's a problem which medication is the culprit. Well I'll push back and say there is no objective evidence that simultaneous rapid sequence initiation increases the risk of medication intolerance, it is considered the patient, for example, what we do with our patients hospitalized for acute M. I. With new LV. Dysfunction in the span of a garden variety patient human dynamically stable 2-4 days in the hospital. They were initiated on dual anti platelet therapy. Staten ace inhibitor, beta blocker and mara. We don't think twice about it. We don't say let's start some of those therapies and just deferred outpatient for some of those therapies. So I think we need to think about heart failure in the same sense of urgency as that acute M. I. L. V. Dysfunction patient. But some other keep comments for context here is that simultaneous a rapid sequence initiation? I think it's feasible because tolerable. Itty will be enhanced if we initiate low doses at 1st 3.125 carvedilol 12.5 of spironolactone in the light. Also recognize that s the LT 200 camera, so two of the four quadruple therapies rarely cause symptomatic side effects in and of themselves. And it's also important to recognize and this is perhaps most important that the worst thing hef ref disease state may be easily mis attributed to a medication related adverse event in that disease state, worsening is more likely if initiation of any of these four medications is delayed. Look on the right here is the example with sclC two inhibitor versus placebo on the odds of a change in N. Y. H. A. Class. You say. You see a patient at clinic today, they're N. Y. H. A. Class two. They're eligible for therapy but you differ you increase the odds substantially that next time they show up in just one month that they are N. Y. H. A. Class three and now you're on the slippery slope of saying well is there were seeing clinical status because they're now intolerance their beta blocker. Don't need to withdraw the beta blocker when in fact the worst thing functional status may be related in the deferral in delay of the therapy at the last clinic visit. So also there will be hesitation potentially for rapid sequence simultaneous initiation because people will say well there's no dedicated RCT of this approach. How do you know that it will work And I will acknowledge that that is absolutely correct. There is no dedicated R. C. T. But in the absence of that definitive evidence from a dedicated R. C. T. Let's consider the evidence we do have. Well there is no evidence that delaying initiation of any pillar of quadruple therapy in an eligible patient accomplishes anything beneficial. And there's no evidence that it improves medication tolerance. In fact I showed data a couple slides ago that it might actually improve medication tolerance if you start them simultaneously. But also instead let's consider that there is evidence that delaying initiation of quadruple therapy needlessly exposes patients to excess risk of one clinical worsening and death and also the possibility of never having the medication prescribed at all as we showed earlier in the presentation and I think what this comes down to is rapid sequence or simultaneous initiation seeks to treat heart failure with a sense of urgency that it deserves. And you know, we often talk in academia about heart failure having a prognosis comparable with cancer. You know, and that's true when you look at the hard data, but the culture of care and the public perception for cancer and heart failure is markedly different patients with heart failure patient in clinicians are overly optimistic and estimates of survival for heart failure patients also, I think both patients, clinicians get distracted with just the short term symptomatic relief that comes with diuretics and this distracts from the importance and urgency of the disease modifying therapies that are so, so important. And also we seem to have a very low tolerance for any real or perceived side effects of treatment for therapies that are proven to reduce all cause mortality very low threshold to discontinue these therapies. So I think the sense of urgency needs to be addressed. And I think rapid sequence or simultaneous initiation is one way to address that and then also understanding these risks of heart failure therapy in the sense of urgency. You know, whenever you're talking about a therapy with the patient, you know, the thing, I think there's a natural focus to talk about. Well, what are the risks of side effects? What could happen? What could go wrong if we start this therapy? What could go wrong if we rock the boat in this patient who says I'm feeling okay today. Well sure there are of course with any medication change for any condition there's always risk of side effects and adverse effects. Um That is that we're not as unavoidable. But I think we also need to recognize to have true informed decision making. We need to recognize the risk of omission. What is the harms of not at least trying this medication proven to decrease all cause mortality, improve functional status. And again the harms are shown on this slide. The harms of not trying are decreased survival, more hospitalizations, decreased quality of life and more symptoms. Yeah. So in summary trying to wrap up the key points for today. Every landmark hef ref trial that has reduced mortality has aimed whether they got there or not. They've aimed to titrate therapy to the currently recommended target dose. So we likewise need to aim to do so in our clinical practice there are also major gaps in G. D. M. T. Both use and dozing in our current outpatient practice. But I will say that closing these gaps is not futile and there is compelling evidence that we can indeed do much better. And then I think of things that we can do today right now in hospital initiation of G. D. M. T. S. But also consider simultaneous or rapid sequence initiation to break that clinical inertia and treat heart failure with the sense of urgency it deserves. And then also, lastly in likewise need to recognize that the stakes are high for not escalated. Have free therapy as maximum tolerated. Think of those risks of omission and that implementation science in a culture shift are needed so we can take full advantage of every therapy proven to improve patient outcomes with that. I thank you all very much for your attention and be happy to take any questions. A fantastic talk. That was really a great overview and really highlights so many things that we need to overcome as a cardiology community for these patients. It's an exciting time that we have these therapies and I think we have to better utilize what's available to us now. Um for folks on the on the call, please feel free to leave any questions, comments in the chat or the Q and A tab. I'll be moderating those. The CMI code once again is 70678. Uh and steve, I'm gonna start off with a few questions here and we'll let the audience chime in as well for rapid initiation, especially when patients are leaving the hospital. The two arguments I've heard for why it doesn't happen more. Our one cost, it's very easy to prescribe it in the hospital. It's harder to transition that to the outpatient setting, especially for some of the newer medications and the second being if there is a side effect or an adverse event, it's then very hard to pinpoint which of the medicines it is if several medications have been started simultaneously. Can you comment on that? Yeah, no, absolutely. In the points that I've certainly heard before, you know, I think for first the cost issue. So absolutely we are newer therapies, cubicle Valse rNS ability to inhibit our cost is a barrier to some patients for sure. But I think first of all, I'll say that costs can't be first costs can't be thrown as the reason for the whole failure of GM because there's so many gaps in our generic medications right? Showed from champ HF first of all one and three eligible patients not on beta blockers, two out of every three non camera. So costs are clearly not at play there. So even among our generic therapies there's significant gaps. So it's not all about costs overall, but I will say in terms of cost for those two particular therapies, the newer therapies, you know, the resources in the hospital are generally much more advanced compared to outpatient clinic. So if there's ever an opportunity to leverage the case manager, all the resources that bear to try to get access to that medication, it's during the hospitalization, deferring to the outpatient clinic and in expecting the prior off to get done and all that stuff. I mean sure. I would hope it could happen. But it's certainly generally easier from talking to people in my own clinical experience to do this in the hospital in terms of the resources that play to try to ensure access to ensure it's going to be affordable. Um So that's that question on costs. In my perspective, you know, the second point about, well if you start all the therapies at once, how do you know which one causes a side effect? And yes, I think sure theoretically that is absolutely point well taken. But I think again, I bring back the example of an acute my patient, right. We just don't even think about it when a patient was on no medications, they have a steamy new LV dysfunction, their humanity stable there in the CCU for a day, they're out of the hospital in three days. They go home on a long list of new medicines. And we just reflexively have no problem starting all of them at once including an ace inhibitor beta blocker in an M. R. A. If there E F is low. So I think we do it there. It's almost like there's a double standard but now we're so hesitant to do it for a heart failure patient. And I think recognizing the risks of omission, sure, adverse events can happen. But I think starting low doses of these medications at first then maximize tolerable ITty get them on board. There are benefits of these low doses. Um and then recognizing again the risk of not starting them is that they're never going to get started and that you expose your patient excess clinical risk. So sure there's always risks with trying things. But the risk of not trying, in my opinion are on average substantially greater steve. The next question has to do with medication type penetration. I'm going to ask you a two part question. One is what are the barriers to titrate nation? Is that knowledge? Is it resources is a time. And then the second part of that is at Duke. How do you guys manage medication titillation? Both as a heart failure doctor and then for the general cardiologist or even the primary care doctors out there. Are there mechanisms in place to help with medication titillation? Yeah, no great questions. So in terms of the first question on, you know, why don't we titrate? You know, I'll be honest with you, there's really no definitive evidence for why not, why are we not doing it? Whether it's is it true intolerance, is it true? You know, cost issue? Is it true patient refusal. Um You know, when you look at data on a large scale nationally, um we don't have those data and it's obviously such a central issue. That's that's a big area for future research and champ HF. We looked at patient reasons for discontinuation. I mean we looked at reasons when medicines were initiated and we looked at medicines when they were reasons when they were discontinued. But the key Russian is well, what's the reason for making no change? You know, that that's the missing element there. That's the reason that I think we really need to get at. Um, so I think the data in Champ again indirectly support clinical inertia indirectly suggests that hey, there's patients walking around with blood pressure's 130, in normal renal function on very low doses of Wrasse inhibitors and beta blockers. I think indirectly suggests clinical inertia is falling asleep at the wheel. But I think there is a need for granular data to more definitely dissect what proportion of patients, proportion is patient refusal or cost or system barriers etcetera. And then the second part of your second question you have, I think was, you know, what do we do at Duke um to try to improve this? So we've done a few, you know, I think we still have room for improvement at Duke were by no means perfect with this. And you know, some of the things that we've done most recently in terms of Q I for G D M tr one we have initiated what I call is an impatient dashboard in the last year for Gmt. So our impatience, it kind of makes front and center on one screen. The list of the core therapies that are disease modifying therapies for hef ref the relevant, the most relevant vital signs the eyes and nose, the most recent labs and the most recent injection fraction kind of just like dumb it down for you to try to make it very simple. You know hey what's actually going on here. I know we're talking about diaries. Is and you believe me over here but hey let's just look at this screen and say it's an opportunity to augment things. Um also in the outpatient setting. We've also started just in the last month. Um and I'm proud of this. We you know as part of the team that really initiated this outpatient um you know so so to speak report cards for our providers um you know not not doing competition where we can all look up each other's report cards and everything like that but really just showing your own report card versus the section. Heart failure section as a whole and saying so how are we doing as heart failure section? And where do you stand? Um as you're on your own G. D. M. T. Now the issue there is that from an EMR perspective is sometimes hard to tease out. You know if you try to medication in the past and they didn't tolerate it or you know if they do have an absolute contraindications that's easier to find. But relative contraindications let's say you have like four relative contraindications, you know does that hold up as much weight as one absolute contraindications you know but but at least at face value gives you a rough idea of where you stand, we can all do better with this. and I think at least understanding your own data is the way to start steve right now. You know at the time of hospital discharge heart failure patients there's a metric they have to go home on a beta blocker and an ace inhibitor. And if they don't you have to document why is there are talks or plans to expand what the metric includes inter and kind of discharge now that we have newer therapies or we're not quite there yet. No I think so. I think so. Um and you know there's there's updates on quality and performance measures um document that came out included Arnie for example in it. Um you know so I think in the new the new guidelines for the A. C. C. H. A. Aren't out yet but they'll include SQL T two inhibitors. Obviously the sc guidelines just came out with you know talking about S. E. L. T. Two is included now for quad therapy. So I think we have to wait a little bit for you know american us guidelines to be updated. Um But yes I think for sure it's only a matter of time and it should be because you know for all the emphasis we get on 30 day readmission. You know we talk about things like okay early post discharge follow up calling the patients make sure they're doing okay. I'm not saying don't do those things but I think the emphasis they get is disproportionate to the evidence behind them, whereas the evidence for preventing early post discharge readmissions as much is very strong for quadruple medical therapy. And I think that's where we really need to focus on the meds again. The other stuff is fine, but the other stuff is kind of generic empirically. No talking that you do that for all your sick patients potentially call them a lot after they leave the hospital, see them early after follow up. But really the core disease modifying therapies for Jeffrey really need to be emphasized couple of drug questions where? Uh huh. Samir, can you you frozen? Samir. It's I think we lost him. I'm sure he'll log back on and I couldn't tell if it was him or if I was disconnected? No, no, he just disappeared. Um Let me contact him. Just give us a minute, but he's back down. I'm sorry about that. I think I think I lost our wifi signal here at the hospital or computer signal. Sorry about that. Um I think the last couple of questions here. I'm not sure if it actually made it over to you. Where does vera sig what enter in your treatment plan? Yeah. So, so Great question. So um. Barisic what was proven to decrease by 10% relative risk reduction. The composite of CV death or heart failure, hospitalization, in the Victoria trial driven by lowering the risk of heart failure, hospitalization. Um you know, and it was also in a population that had a worsening heart failure event recently so patients that were within six months of a prior heart failure hospitalization within three months an outpatient ivy diuretic visit that were already on good GMT. So the way I think about it is that I think the core four pillars of GMT that Arnie the beta blocker, the mara, the sclc to those are proven to decrease all cause mortality. Those have to be prioritized now for people. But unfortunately even with quadruple medical therapy there is a substantial residual risk that our patients have. And I think for those therapies that have worsening heart failure events that are already on good quality therapy or that are not able to tolerate some of those for disease modifying mortality reducing therapies. Then we need to think about therapies like various sig what um Similar I think the situation will be for OMA Captain McCarville who's not, not FDA approved yet but it was tested in the galactic HF trial. Um This is a therapy that I think could be important for residual risk and select patients with maybe more severe heart failure. Um You know kind of similar to viruses. Whopping first. Maybe select patients with the worst and heart failure event. Do you lean towards using natural law versus carvedilol in patients with borderline blood pressure. So you have more room to titrate. Is there one beta blocker you prefer for the other? Yeah. You know I know anecdotally. We all use that across cardiology. We always equate bento brawls being less blood pressure effect. And carvedilol being um more blood pressure effect. You know, I generally favor carvedilol to be quite frank. Um You know I favored meta brawl sometimes just for the one day adult one once daily dose is more than the actual blood pressure effects from the easy use for patients that I'm worried about taking twice a day medications. But when you actually look at the data for carvedilol, you know, in heart failure, um you know, I was tested in the Copernicus trial which is people with very severe heart failure and was actually tested a subset of patients with systolic blood pressure of 85 to 95. And in that subset of people with hypotension, it actually compared with placebo, it actually tended to increase blood pressure Or it didn't definitely didn't lower blood pressure. So I mean again 3.125 Coreg. You know, it's pretty human dynamically neutral itself. And I think it's 6-1 half a dozen. You know, Again, one in three eligible patients don't get any beta blocker at all. I think it's dealer's choice. Which which evidence based beta blocker you want to use. All right, one last question for you here and then we'll wrap things up. Uh Again, we really appreciate you coming online today. This has been a great talk in a great discussion. Um In the emperor reduced trial. Um trying to look at, it looks like what percent total death reduction was there. When you look at an SGL two inhibitor versus placebo. So for all cause death, it was around 13 or 14%. When you I'll say this that emperor reduced technically didn't achieve statistical significance for death compared with placebo. There was a trend but not physical significance. But when you pull the data together for Dapa, HF and Emperor reduced and get more statistical power, there's a meta analysis in the Lancet. You know, there was no statistical heterogeneity suggesting that trials are more similar than different with their clinical benefits. And when you pull the data for SclC two inhibitor versus placebo and Hef ref talking about 13 or 14% reduction in all cause mortality again, all cause mortality, you know, really, you know, the ultimate endpoint for a drug. All right, well with that we'll leave it. I think we finished right on time and again, steve I wish we could have had you up here in philadelphia. Uh there's a lot that we could continue to discuss and learn from you. But this was fantastic. Thank you again. No, it's a real pleasure to be here. And thank you very much for the invitation. Really appreciate it. All right. Hope to see you again soon. Take care of one. All right
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