Natriuretic Peptides 101

In this on-demand recording, Drs. Robert Christenson and W. Frank Peacock share their perspectives from the lab and Emergency Department on the value of BNP and NT-proBNP testing. Learn as they discuss the biology, clinical value, and confounding factors associated with BNP and NT-proBNP tests and how they are used in heart failure diagnostics and therapeutic monitoring.

Robert Christenson 

Robert Christenson, PhD, DABCC, FAACC, FACC
Professor of Pathology & Professor of Medical and Research Technology
University of Maryland School of Medicine

Frank Peacock 

W. Frank Peacock IV, MD, FACEP, FACC, FESC
Professor of Emergency Medicine and
Vice Chair of Research for the Department of Emergency Medicine
Baylor College of Medicine

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Speaker Speech
00:00:00:00 - 00:00:37:12 Doctors Christensen and Peacock. I have a set of questions for our MLO audience on natriuretic peptides. And my first question is what considerations are factored when deciding between BNP and NT-proBNP?
Rob, you go first. Yeah, I'll go ahead. I tell you one of the major considerations is the large analyzer that you use in your medical center.
00:00:37:14 - 00:01:09:19 If you use analyzer in your medical center that does BNP, then certainly BNP would be much easier for you to offer to your clinicians. If a platform offers NT-proBNP then vice versa. So you'd have to have a pretty compelling reason to just switch from one to another. In other words, to take samples off a track, for example, or off of your large analyzer and put it on another analyzer for that value.
00:01:09:19 - 00:01:43:05 So that that is a major consideration. That said, I believe that the convenience of NT-proBNP for a number of reasons, such as stability, such as the cutpoints etc. really favor NT-proBNP. So a lot of the big box analyzers offered by a lot of the large manufacturers if they have in the past offered BNP they're switching to offering an NT-proBNP option.
00:01:43:07 - 00:02:08:23 So in any case that's a major issue from the lab perspective anyway. And from the ER perspective we do at the lab tells us to because I have no choice on what analyte my hospital does. These decisions are made by the lab guys based on cost and, you know, the size of the big box in the basement.
00:02:08:24 - 00:02:27:13 And I can complain about I want something different. And there's physiological reasons to choose these. The most important one is the one you have been using is the one you want to use because you get used to that. And I don't mean that you get just used to it because you're familiar with it, but you get used to it because the patient comes in and they tell you My result last time I was here was 700.
00:02:27:15 - 00:02:44:22 And if you don't know what you're using, you have no clue what that means. So you do get used to what you have. But as to the decision that’s Rob. Well, I don't know, Frank. I think you're selling yourself short. You know, I wouldn't be in this field very long if I didn't listen to folks…
00:02:44:22 - 00:03:06:03 On the clinical side say. So we listen about a lot. And really even some of the issues with heart failure and some of the treatments that we'll talk about a little bit later, we certainly have to have a dialog between the clinicians and the lab to get the right one for treating the patients at our institution so nicely to say that.
00:03:06:03 - 00:03:34:02 But we certainly listen to you very carefully. Haha, go ahead and say that again. But there's a couple follow up questions I have on this topic. Also, are there patient conditions where you may choose one over the other and what are the benefits to having access to both NT-proBNP and BNP? Well, maybe I can take it first because I'll have a very short answer.
00:03:34:02 - 00:04:00:11 So there are some treatments. One blockbuster is Entresto that there was a lot of press about the fact that being BNP was elevated by this by this drug is part of how the mechanism of this drug works. So that was one issue. I don't know that that has really become so important clinically. So I'll ask Frank that question.
00:04:00:11 - 00:04:32:19 Do you think that difference is a game changer for which analyte we would offer BNP or NT-proBNP? Not for the ER, because on the diagnostic side that doesn't really have much of an impact or either molecule, doesn't matter NT-proBNP or just regular BNP because you know you've got as long as you know what your assay is, you've got a set of guidelines that have been validated in huge numbers of patients that tell you if it's above this level that they're really likely to have heart failure or below this level, you're really not.
00:04:32:21 - 00:04:54:01 You just need to know which cut point you're using. So when a patient comes in on Entresto, yeah, they're slightly elevated, but does not rise to the level of pushing them to a new diagnosis they didn't already have or a standard. I think the only place that that that becomes an issue is when you've got a patient you're changing over and you've been follow them closely.
*Disclaimer: Access BNP and NT-proBNP assay performance has not been evaluated in patients taking Entresto.
00:04:54:02 - 00:05:12:20 And not all docs believe that natriuretic peptides are valuable to be used as a endpoint in titrating therapy. I'm one of the ones who do, but I apparently I'm in the minority. But if you believe that and you and you're messing with the patient's drugs and they're having a response, and in the middle of that you add Entresto.
00:05:12:21 - 00:05:32:01 So and now they're BNP goes up a bit, you're going to go, Hmm. And do I need to re-titrate my drugs or do I need to just consider the assay? And so you have to know that and follow it. And I think some people say these are huge changes. And in my observations it’s, 5% or 10%.
00:05:32:01 - 00:05:58:01 It's never huge. But it is change, but not for diagnostic point of view. Right. And I think that we're in one in some ways, we're pretty fortunate that heart failure really makes the difference between a normal value and a high value very substantial. It's not a subtle difference like calcium or maybe some other things might, but some other analytes might be.
00:05:58:02 - 00:06:28:00 So that kind of serves to underscore exactly what you've said, is that it's not a subtle difference like what you might see between Entresto or non-Entresto. It's really the acute illness of that patient. Thank you. That was very informative. I have another question on what is the importance of turnaround time for cardiac STAT assays and what are some ways to expedite them?
00:06:28:02 - 00:06:51:14 Well, this is the ER world and I'll put it to you this way. I collect data on patients and I have data on more than 16 million patients based on the time they were in the emergency department. And as little as an hour delay increases mortality regardless of the severity of illness, because the E.R. is not meant to have maintenance issues.
00:06:51:16 - 00:07:10:07 I'm dealing one guy and I'm trying to figure out who's diagnosed. This guy over here is having a seizure. I was at turn turnaround to deal with that. And the more of those patients I have clogging up my ER, the big of a problem is the quality care goes down, we can get overwhelmed and that's our challenge. And so if you can tell me I'm going to test an hour quicker, that's a big deal.
00:07:10:09 - 00:07:29:00 An hour doesn't sound like a lot, but it's not just that time. It's the time for everybody in that department because I discharge somebody that's one more bed I didn't have before. And it's also patient satisfaction issues because nobody likes to sit around the E.R. wondering. Everybody in the ER thinks they're going to die. I mean, that's why they came.
00:07:29:06 - 00:07:46:19 The food ain't that great. They don't come for the food. And so they are all nervous and anxious and their family is and if you can solve their disposition, they don't even mind being told they're getting in a hospital. They just want to know what the what the issue is. Am I going home and am I stay? That's the critical piece.
00:07:46:21 - 00:08:10:09 And so patient satisfaction goes through the roof, if you can tell them. And there was a study done by Press Ganey. These are the people that who do all the surveys on how much they like us and in which we receive billing and said efforts with to as well. So in over a million patients, the magic number is 4 hours.
00:08:10:11 - 00:08:27:12 If you pass 4 hours, the I am not satisfied rate goes up from 25% just starts going right up if you're under 4 hours, everybody loves you. So that's sort of the magic number. And if I had a lab test, it takes an hour. You just took 25% of the time I got. So an hour is a big deal.
00:08:27:14 - 00:08:50:13 Rob… Right, well, this is why it's so important to listen to our clinical colleagues. You just see what all the different perspectives are. And I think we're in this era of evidence based medicine. There have been a couple of trials that have shown that patient outcomes actually are better if you have a more rapid turnaround time.
00:08:50:13 - 00:09:20:06 I think probably it's one vector and what Frank might take to put himself in one direction or another for taking care of a patient, but getting us that out of the lab, getting this natriuretic peptide value back does have value. And as Frank says, there are many stakeholders here. There's the patient, the patient's family, there's the emergency medicine folks, there's a whole host of stakeholders that I think nobody would argue against.
00:09:20:06 - 00:09:56:13 A faster turnaround time as long as it wasn't prohibitively expensive to offer that turnaround time. What is the frequency of natriuretic peptide assays being run as STAT assays? So that would be a Rob question, I'll pitch a little bit, but then I'm going to hand it over because he has the bigger hospital perspective.
00:09:56:13 - 00:10:16:24 I tend to be biased to the E.R. and I'm biased to heart failure, which is an area of my research. I think the data is pretty clear that the sooner we can figure out the diagnosis of the patient, the better they do in acute conditions. Your stubbed toe could wait a week, but if you're short of breath from heart failure, probably not.
00:10:17:01 - 00:10:45:04 And so I consequently feel that there is value in rapid natriuretic peptide testing because it moves that needle to, oh, you have heart failure as your shortness of breath problem. It's not COPD or whatever they thought it was before. And then they get heart failure treatment, which does change their trajectory. There are some markers that are more important than others troponins and that natriuretic peptides are the big ones and probably a d-dimer you can throw in there.
00:10:45:06 - 00:11:08:07 The rest of them, I don't really care if they take a while because I can sort of have a feel for that, but these are ones that do move you quickly down a treatment pathway and it is not common for natural peptides to be static, it just isn't. Everything in the here is STAT, but then there is we do it point of care which makes it 15 minutes versus the central lab does it, which makes it an hour.
00:11:08:09 - 00:11:37:19 And so that that, that difference, it depends on the severity of illness of the patient And so if you lump all the heart failure patients, you know, half of them are really severe and half of them are not the half that are severe would benefit. And I would say that other than OR and probably trauma. I think the E.R. is an area taken care of urgently, currently ill patients acutely ill.
00:11:37:21 - 00:12:10:02 And so that area, we treat everything from that area STAT. So I would say that just that everything we can offer. Now Frank brings up a great point in that the way to really make it so you can do it quickly is to do it at point of care. So we have we do not currently offer NT-proBNP at point of care like we might offer some of the other analytes like troponin or calcium or some others that can be acted on immediately.
00:12:10:06 - 00:12:36:20 But we do offer a turnaround time of less than one hour. So I would say all of our analyzes that we provide to the to trauma and to the OR and to ER are what we would call STAT. Thank you. When you're interpreting natriuretic peptide values, what are some of the key consideration items that you feel are underappreciated?
00:12:36:22 - 00:13:22:17 So maybe I'll start so Frank can really go into it. But I think the negative predictive value of NT-proBNP or BNP is valuable because the biomarkers really are linked to hemodynamic stress from any cause. So heart failure is by far not the only condition that can show increases in an NT-proBNP or BNP, but so we have to keep in mind that it's a very sensitive marker in its increase, but it's not a very specific biomarker.
00:13:22:19 - 00:13:48:19 What I mean by that is just because you see an increase doesn't mean that that patient has heart failure, right? It's probably 50% specific and over 90% sensitive if you know what that patient has to follow. So I'll hand it over to Frank for those basic comments. You know, that's really an important thing that you brought up, is that it's not a heart failure test.
00:13:48:21 - 00:14:07:11 It's a wall tension test. So a giant pulmonary embolism, a heart attack, all these other things that can cause wall tension can also cause an elevated BNP. And if all you did is look at the number, you're not going to be a very good doctor because you're going to blow a lot of the diagnoses. As a rule out, it's outstanding.
00:14:07:13 - 00:14:27:03 In the very first trial that was published 25 years ago, the negative predictive value for a BNP under 100 was 99%. That means you've got to come up with another reason for their shortness of breath. You probably got it because they were short of breath, but now it's something else. Asthma or something of that nature. So that's very useful.
00:14:27:09 - 00:15:01:19 There are also the other confounders that screw this up, which is obesity causes a lowering of the BNP falsely. So if you see a morbidly obese person who's BNP is half of what you would expect it to be, they probably get hearts in a two year cut point. So probably heart failure. And the converse is that renal failure because there is a level of metabolism there of natriuretic peptides when it is when patients have renal disease and they're on dialysis or just have bad kidneys, the natriuretic peptide levels will be elevated.
00:15:01:19 - 00:15:26:01 And so you have the sort of weigh those two. Those are the two major confounders to making an accurate diagnosis for the patient who shows in with a natriuretic peptide level because if you don't put it in context of body mass and renal function, you're going to be very confused by the results that you get.
00:15:26:01 - 00:15:54:11 Right, and certainly from the lab, the same thing. We see actually very elevated values with renal insufficiency. Frank, do you think it's linear? In other words, the morbidly obese person is going to have a very big value. But somebody who's only got a BMI of maybe 35 or 40, would that still have they have an impact on the values.
00:15:54:13 - 00:16:16:15 So I actually like this story. So one of the ways that BNP is metabolizes by C receptors on endothelial, it's not the only way, but it's an important one. And every pound of fat you add adds a mile of capillaries, in other words, more endothelium. And the way I look at it, more fat you have, the more eating machines, the more you eat your on BNP.
00:16:16:17 - 00:16:39:14 And so it's lower. So it's proportional. If you're 700 pounds, you probably have a lot more miles of capillary than somebody who's 180 and five foot tall. So there is that relationship as well. So you have to sort of sort that out. There was a formula that was done years ago trying to sort this out where if the being BMI is over 35, so obese.
00:16:39:14 - 00:17:00:06 You’re supposed to double the BNP. My experience is it doesn't work very well. It works around that number. But when you're up to 500 pounds, now you're off the charts. So at some point you just have to use your brain that you know, that you're getting falsely low results and calibrate proportionately.
00:17:00:08 - 00:17:23:09 The same is true with renal failure. When your GFR is below 60, you start to have clinically relevant changes in natriuretic peptides. And the rule that I was told, Alan and myself published years and years ago, which was when the GFR is below 60, you're supposed to half the BNP, but it's the same story as body weight around that cut point.
00:17:23:11 - 00:17:54:20 It's okay, but when you're really extreme, when you're on dialysis, the BNP is a nightmare. So the instructions should just be consider this and consider more at the extremes. And I think interpretation wise, it's really important to remember that what we're dealing with here is a hormone, right? I mean, this is a hormone that's reactive to how much how much fluid is on board and maybe in other kinds of stress.
00:17:54:22 - 00:18:17:04 And so that that sort of rule of thumb with that it has to increase by more than double and decrease by more than half to be a real change. Do you find that sort of rule of thumb to be useful clinically? I actually do like that one. The RCV, the relative change value is the description of how much of what you are measuring changes every day as a point of normal physiology.
00:18:17:06 - 00:18:39:19 And we see this all the time. A patient comes on heart failure, their BNP will be 700, you know, that's clearly heart failure, but it's not ridiculous. So we put them in the observation unit and we treat them aggressively and the output is two liters by tomorrow, and they're feeling a lot better. Their BNP will drop, you know, by 50% in the next morning, at which point you're comfortable sending them home.
00:18:39:19 - 00:18:57:24 And if it doesn't move that much, then I worry. And we are able to show that if it doesn't move by at least 50%, and you send them home, they'll just come back. As if it only went from 700 to 500. You would be you would be concerned that your therapy and your management hadn't had the impact? I Don't think you've moved it enough.
00:18:58:04 - 00:19:22:21 Yeah. That also works diagnostically because we see people all the time. They've been in the hospital for a week, they get sent home, they come back in two months and they're short of breath and you got to say, well, is this short of breath the day because they've got pneumonia or is it the shorter about the day because the hardware has gotten worse and you can't always tell. X-rays of heart failure patients are really difficult because there's just sort of this white mass and do they have pneumonia in there?
00:19:22:21 - 00:19:41:05 The answer is always possible. So you're trying to sort that out and the number is that it should double on the way up. So if they normally are at 500 and they come in at 700, it ain't heart failure. If they come in at a thousand, it's probably heart failure. But if they're just a little bit up, heart valves may contribute to their problem.
00:19:41:07 - 00:20:02:20 But you better think of something else because it's not the sole problem they're having when they came to the E.R. today. You know, I wanted to ask you about something or talk about something for a moment. So it's been about almost like a 20th year anniversary since the first BNP or NT-proBNP assays became widely available.
00:20:02:22 - 00:20:34:24 And so our assays have intentionally stayed very consistent, very constant over time. And yet the interpretations have slid more, maybe because we've learned more about co-morbidities and other conditions with this. Maybe because we have better treatments. So we've sort of stayed in one place with the analysis of it. But do you think that the treatments of heart failure, for example, have evolved and maybe more attention to hypertension and, you know, all the new.
00:20:35:01 - 00:21:02:21 It used to be your age over 100 or something, it was your normal blood pressure. Well, now it's a whole lot different than that. Do you think our way of treating diseases has really evolved over the last 20 years in the context of what we might interpret NT-proBNP values as? Absolutely. I'm trying to think, 20 years ago, we've added three classes of drugs.
00:21:02:23 - 00:21:31:17 So that was about the time that beta blockers became mandatory. And before that it was like beta blockers. They'll kill patients, don't get that heart failure patients. And now it's mandatory. It's a 1a recommendation. If you don't do it, you're sort of a quack. So all your patients are on beta blockers. And then now and recently we've added in the neprilysin antagonist, Entresto being the most common available in the US, which that increases your BNP but not your NT-proBNP level.
00:21:31:19 - 00:21:56:24 And that is a mortality reduction. So it's a1a recommendation you should be on that. Otherwise your doctor's not very good. And we're adding SGLT2 inhibitors which are also a new one and that seems to have some benefit across the board regardless of just your ejection fraction, whereas the others are stratified by ejection fraction. And so yeah, it's gotten way more complicated and each one of those classes of drugs has several drugs inside of it.
00:21:56:24 - 00:22:19:05 So we've added a boatload of opportunity. And the nice part is every one of those things is another, you know, 15 or 20% decrease in mortality. Our outcome benefits are phenomenal. We're doing things now that you couldn't believe happens like ejection fraction are getting better. And now there's a controversy of what happens when you had a patient on ejection fraction 35.
00:22:19:05 - 00:22:42:00 In other words, his lifespans shorten and it's now back to normal. Can you go off all his medicine or does he have to take them and you know people still argue about that but what a great position to be in. It’s like we've cured you to the point we're going to argue about whether we stop your drugs or not. I mean, so, yes, to answer your question, there's been a crazy amount of change in the last 20 years, and that's just the heart failure space.
00:22:42:02 - 00:23:07:15 Right. Right. And I guess one of the things that I've learned over the last 20 years is the difference that really heart failure, I guess, two broad buckets, right, with preserved ejection fraction, which you talked about ejection fraction. And some of these patients have almost like a normal ish ejection fraction and others where the ejection fraction is very low.
00:23:07:17 - 00:23:47:10 One, and there seems to be management differences between those two. Some of the drugs don't work at all on the on the preserved ejection fraction patients is my understanding. Do you think that and to try to detect peptides, is there any difference between those two groups of patients with BNP or NT-proBNP interpretation? Unfortunately, not much. I mean, I'd hope that and when you put out the curves. So the natriuretic peptides are a function of volume overload and a sign of heart failure and, and wall stress and regardless the ejection fraction you can meet those criteria, you have volume overload wall stress, the physiology is completely different.
00:24:10:23 - 00:24:37:04 So the ejection fraction is not helpful acutely because they all look the same. They're all short of breath. The natriuretic peptides are diagnostic in all of them. But for chronic disposition and interventions, it's critical to figure that out. But in the emergency department, the BNP is more important. Right, yeah, it's just interesting to me that we've stayed the same.
00:24:37:04 - 00:25:02:20 And yet the interpretation of this analyte has changed with the evolution of really the drugs that have been available to manage these patients. So that's for sure. You remember the days before we had natriuretic peptide testing. It was heart failure. Why? Because I said so and that was it. And, you know, the published data on error rates was phenomenal.
00:25:03:01 - 00:25:24:10 When you had a gold standard diagnosis of two cardiologists looking at everything, you know, three months later they published data. It was a 25% error rate. It wasn't heart failure because I said so. So but we had no test. And then natriuretic peptides come along and it's completely revolutionized the entire field. So yeah, I remember early on folks saying, We don't need an essay for this.
00:25:24:10 - 00:25:47:18 I have my stethoscope here, I can tell you. So it turns out to be an important help, especially from the negative predictive value side anyway. But it’s been quite an evolution over the last 20 years or so since they became available. Christine, did you have another question you want me to do? Yeah. Can you share your thoughts around the importance of reference intervals?
00:25:47:20 - 00:26:15:12 Are healthy population studies for now natriuretic peptides informative, in what context? Well, I think reference values are always important for every assay there is. If we don't know what it looks like, what the analyte looks like, and BNP or NT-proBNP for example, what it looks like in normals, then it's much more difficult to interpret them in disease.
00:26:15:14 - 00:26:47:20 Luckily NT-proBNP and BNP the values the increases are not generally subtle. Usually they're very large others is different as we talked about briefly before. So having those correct intervals are key and with the because probably at least in part it becomes more complicated with BNP and NT-proBNP because they're hormones. And so there are differences between men and women.
00:26:48:01 - 00:27:16:18 There are differences with age, there are differences, as Dr. Peacock mentioned, with obesity, with renal function, etc.. So I think reference intervals are very key as a sort of a stake in the ground. What a patients would look like if they were within that normal, within that within their normal state of health. Frank? Yeah, absolutely.
00:27:16:20 - 00:27:42:19 You pretty much listed everything I could say, but I will tell you that the age of the United States is getting older. And as that occurs, these natural peptide levels are different and patients are having more diseases they never survived before. We have a whole specialty now of cardio oncology for biomarkers. And, you know, so we have it's not just biomarkers, it's therapy and everything else.
00:27:42:21 - 00:28:08:04 But that specialty didn't exist 20 years ago. And so now we have people walking around with heart damage from the therapy they got to cure their cancer that they survive from. And it's a whole different patient. And knowing what standard is, is important because as this gets more and more complicated, having that stake in the ground you talked about is really critical to know, is my patient getting sicker or not?
00:28:08:06 - 00:28:34:02 Right. I know especially in children, some of the drugs for treating leukemia, for example, were linked to heart or have been. They have a side effect of heart toxicity. I guess biomarkers are becoming more and more important in helping to titer how much tolerance these patients have.
*Disclaimer: For Informational and educational purposes only.
00:28:34:02 - 00:29:0 So yeah, that's some of these chemotherapies eat your heart at just a slightly slower rate than the cancer. It’s going to take a hit, you'll live, and now we’ll have to know what to do with that. I think one of the things that's really underappreciated, though, the difference between men and women. We do adjust the natriuretic peptides for age, but the difference between men and women is almost not quite as large, but almost as dramatic as it is with age.
00:29:02:16 - 00:29:29:05 So hopefully in the future as differences become more important, that we'll be able to use that variable to better refine our reference intervals. Yeah, I mean, that's coming across the entire spectrum. We're doing it with troponin now. Traumatic brain injury research has big differences, so why wouldn’t it be natriuretic peptides.
00:29:29:07 - 00:29:49:04 The single most accurate predictor of whether you use in sex dependent blood points was told to me by Louise Cullen at a talk at the American Heart Association. She said, you know what's the biggest decision is the sex of your lab director? If you have a lab director who's a female you were more likely to have sex dependent, cut points in that.
00:29:49:05 - 00:30:15:01 So we need more women lab directors. Yeah, I think my wife would agree with you anyway. I think we agree that the reference intervals are important, the right ones are important, and we should take into account all of these variables and, and getting the right, maybe personalized reference intervals for individuals. Thank you.
00:30:15:03 - 00:30:43:06 Could you tell us about the interpretation of results and how co-morbidities are in play? How does age factor into the decision-making process? I'll probably have Frank crack at that one first. Well, the older you are, the more your heart becomes stiff and also by sex. This is this whole idea of a preserved ejection fraction heart failure.
00:30:43:08 - 00:31:02:11 Women older women have this more often than men do. And so you end up with cut points that are going to be derived by age. So there's your normals who are 40. And then as you got past some certain age, you need to have cut points that are higher than that, because otherwise you're going to call everybody who's old having heart failure, which they don't.
00:31:02:13 - 00:31:39:23 And then you're going to stratified that by sex. And so all of these become part of the matrix of your diagnostic tool that you're using. And whatever one assay you're using, they all have a matrix when they got FDA clearance that you can look at and then that maximizes your accuracy. Yeah. And I think, you know, I think back to the sensitivity and specificity of the biomarker, the specificity, that 50% means that it's elevated in a lot of different diseases.
*Disclaimer: NT-proBNP may not be cleared in all countries.
00:31:40:00 - 00:32:12:22 So I think co-morbidities of lung diseases, etc., anything is going to impact the lungs, is going to cause hemodynamic stress. And that wall of tension, as Dr. Peacock talks about to increase and so it’s going to be a confounder. And boy, there's been there's the list of diseases that can have increases in BNP and NT-proBNP is long and will probably get longer in the future.
00:32:12:24 - 00:32:35:02 It's still a good rule out. If it's low then yeah, but if it's high you have to put on your brain and use it because otherwise you'll be wrong in a significant number of patients. And that's where that negative predictive value comes in. If it's low, then really the value is pretty good.
00:32:35:04 - 00:32:56:24 Yes, there are some exceptions like obesity. But anyhow, when it's elevated though, it can be very nonspecific. Yeah. Are clinicians looking at cutoffs with relation to comorbidities and are they looking to optimize the cutoffs?
00:32:57:01 - 00:33:21:10 Well, you know, earlier I talked about those formulas that were promoted early in the era of natriuretic peptides. The trouble is, is that it's one size does not fit all. The more extreme you are on, either on your renal failure or obesity the less the natriuretic peptide reflects your hemorrhagic state compared to somebody who does not have renal failure or obesity.
00:33:21:12 - 00:33:42:21 And so you have to take those in consideration. I suspect, in the AI world we will eventually come to the point where Rob will have a computer, report a result, that that takes into consideration these other parameters. But I've never seen that. And the formulas that I've seen produced so far are only good in a narrow range of abnormalities.
00:33:42:21 - 00:34:06:11 And as you start moving into the characteristics of human beings they’re not follow the rules. When you get further extreme away from that initial cut point, they become more challenging. When are you getting the computer Rob? Well, I tell you, it just reminds you, I think we are in the age of algorithms and use of computers and all that.
00:34:06:11 - 00:34:33:23 But so they are they're helpful aids and they can probably come up with a probability. Right. That that it may be one thing or another. And when the probability hits 100% then then that's when the computers are really good at it. But it takes the gestalt of a human being, I think. And not only that, but the ability, like you said, to listen to the patient, listen to their family and see what situation they’re in.
00:34:33:23 - 00:35:09:07 And I don't know. They haven't gotten the humanitarianism algorithm done quite yet. But, I still think our computers are valuable. But you think about why clinicians order tests to try to rule in or rule out and try to refine their thought process of whether what's the likelihood of that disease being present and then what would be the then after they get that end result, they can, they can consider the management strategy that would be best for that individual patient.
00:35:09:09 - 00:35:26:15 Yeah, I mean, the most important piece here and computers don't win, is the entry criteria that made you obtain the test. Because if you just go out in the waiting room and you get a bunch of natriuretic peptide levels on everybody sitting there, half of them are not patients, staff, some are just family members waiting for patients.
00:35:26:17 - 00:35:44:01 You'll find that some of them are elevated. I don't know the slightest clue what that means. I would have you follow up with your doctor if I knew that, because you probably should have your hypertension fixed or whatever else is contributing to your situation. But when you have a patient who is short of breath, that's where this becomes really valuable.
00:35:44:01 - 00:36:01:09 And the computers have trouble with this. You know, I can listen to you and you tell me you're short of breath or I can hear you wheezing. I know what some of the issues are. You have to know that before you draw the test. So I think there's definitely a place for computers and algorithms in medicine.
00:36:01:11 - 00:36:36:16 And that's a little bit like what we were saying. It's just you can't rely on everybody's experience and specialty is not the same. So it is important to have that standardization or a probability, but there's no there's certainly is no substitute for experience at this point. Anyway, thank you. From your perspective, what has changed most significantly and use an interpretation of natriuretic peptides in the past five years?
00:36:36:17 - 00:37:04:14 I think it's just knowledge. I think it's the number of what some studies have been done like the ICON study, Ikon reloaded that has seen maybe the impact of both disease and we know the biomarkers have not changed but the diagnostic use of them may have.
00:37:04:16 - 00:37:26:16 Oh, no, I didn't have a great answer. I was going to say what we said before, which is that the Entresto feature, that is the only new thing that really directly affects the interpretation of these levels. And after that, yeah, it is, we've just gotten smarter. I looked at the number of publications on Natriuretic peptides, it's tens of thousands.
00:37:26:16 - 00:37:56:19 It's unbelievable. So we've learned a lot. But in the last five years there's nothing been really Earth shattering, I think, except for the Entresto business. And heart failure is I think, the very safe to say that it's a sort of disease of the elderly, right? The prevalence is much higher. And when do co-morbidities, when do other disease entities start coming in, well, the older you get, you realize you're taking more medications.
00:37:56:19 - 00:38:19:06 You there's more things that go wrong. You can deal with one thing at a time, but when you get several going at one time, it is more complicated, as I can tell you from personal experience. I’m not a young fellow like you Frank. I think these are all things to be considered and our population is getting older as well.
00:38:19:06 - 00:38:54:18 So we all know that's true. So thank you. From a forward looking perspective, how do you see heart failure diagnostics and the use of natural peptides evolving ten years from now? Well, I think that there's going to be a lot more using them as the barometer for the patient's health. So you're going to go in and you're going to have your natriuretic peptide level obtained every time you see your doctor, if your heart failure patient it’ll be every time you see them and they'll adjust your medications based on that.
00:38:54:18 - 00:39:16:09 I think the literature supporting that is not the strongest at the moment, but I think it's got plenty of signals that if you follow the rules, the patients will do better. And so I look at that as becoming a real opportunity. We're also seeing wearables. You know, we're doing diabetes now, but there's things people wear in their arms and they follow their sugar and their phone then talks to it and can manage their diabetes.
00:39:16:11 - 00:39:36:17 I look at that happening as well as we go downstream in the next decade or so, because that allows home management. It's a heck of a lot cheaper and it prevents the wild swings of no symptoms till lots of symptoms go to the hospital. No, lots of symptoms go back to the hospital, if you can titrate that.
00:39:36:17 - 00:40:03:09 So it's a little symptom and I titrate it up and then you get better and so would make the patient's quality of life a lot better and probably save us a ton of money because they're not in the hospital all the time. So I look at those kind of interventions happening more over the next decade and there's going to be a bunch of crazy breakthrough stuff that happens, where we can measure troponin transcutaneously, that would be cool.
00:40:03:11 - 00:40:34:08 Just sit at home, call your doctor, say, Hey, it's a 75, what do I do? But, that's looking down the road. So, so I think A.I. and NT-proBNP and BNP and other biomarkers are going to be really important as we go further into the AI era. I guess I'll call it, because they will give you objective information, important physiological information about stress, about the health of your heart, etc..
00:40:34:08 - 00:41:17:02 And I think there's already building literature and there already is a very firm one of one when these analytes BNP or NT-proBNP and troponin is another one that increase in health and that's you're supposedly healthy is not a good it's not a good prognostic sign. Earlier folks didn't get called by their insurance company or by their health provider and saying, oh, you know, you should get a gym, we'll pay for you to get a membership at a gym.
00:41:17:04 - 00:41:43:24 You have to use it and we'll give you a break on your insurance next year if you do. And you know, you don't have to have a co-pay if you you're in this program or another. So I think medicine is going to hopefully become even more important in people's lives. So all of those things together are going to increase the importance of biomarkers.
00:41:44:01 - 00:42:18:09 To my last question is how do you see clinical decision support and other artificial intelligence related technologies impacting heart failure, risk assessment and patient management? Do you see AI ever replacing clinicians? No, because AI doesn’t have a clue. They can only tell you what's been. They can't tell you the future, at least in the current iteration. And it can't look at you and go, that guy looks like crap.
00:42:18:11 - 00:42:45:21 I was really good at pattern recognition. So when you give it a set of numbers, it can say at levels that humans cannot interpret this person as a bad pattern and they need to have an intervention and then you can do something about it. But the practice of medicine is that Gestalt business where you just have a feeling about somebody.
00:42:45:23 - 00:43:05:17 There's not a single number that's bad on them, but you just have a feeling because they don't look like they're breathing right or something. You can't even put a diagnosis on it. But those people and then they up and try to die. And so that's the skill set at least current in the current iteration that computers cannot do.
00:43:05:19 - 00:43:21:22 And quite honestly, it's why you have to do a residency. If you could read a book and be a doctor, then that's what everybody would do. But that doesn't work that way. You have to spend at least three or four years running around looking at sick people before you start to have that feeling. So that's why they do a residency program.
00:43:21:22 - 00:43:41:10 Otherwise you could just do it all by the book and it doesn't work that way. So I think AI will have a huge impact on heart failure because it will be able to tell you that you need to up this guys is ACE inhibitor by 17 milligrams, which would be very difficult for a human to figure that out.
00:43:41:12 - 00:44:05:08 But when you put numbers and objective stuff to it, the computers are really good at that and they will be able to tell us stuff that we can't figure out right now. It'll be interesting to see what happens in the future about things like personal preferences that a physician who knows a patient for a long time can really tell whether they really mean what they say.
00:44:05:08 - 00:44:24:13 They say, well, you know, if can't do this type of thing, I don't want to live any longer. Well, it changes when people get sick later and they find out that you can have a good quality of life no matter what. So how does a computer say, well, you said before that...
00:44:24:13 - 00:44:58:12 So it was it changes with time. I think with personal preferences, nothing will take the place of that human-to-human interaction with the physician I don't believe. Not in our lifetimes, which is long enough. Well, thank you so much. This was very informative and enjoyable to hear both perspectives from a laboratory in and an emergency medicine doctor.

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