Khurram Nasir, MD offers a Grand Rounds discussion of cardiovascular risk assessment and management and the “power of zero,” in risk assessment (a novel and at times controversial concept for which he was a co-creator) that holds that patients with no evidence of coronary artery calcification need not receive pharmacotherapy or repeated imaging studies. Includes a Q&A with Harvey Waxman, MD, Chief, Cardiology Division, Penn Presbyterian Medical Center. Nasir, MD is the Chief of the Division of Cardiovascular Prevention and Wellness at Houston Methodist DeBakey Heart & Vascular Center.
perfect. Yes, me again, thank you so much for the kind of invitation really to share our thoughts and more importantly to get your feedback and thinking on the challenges journey that has shaped our understanding of the role of the coronary artery calcium testing and especially this phenomena power of zero meaning absence of disease and how it has shaped the past, the present and more important in its own in the future of cardiovascular prediction and management force. So for that Samir I would like to take liberty to have you on a slight detour from the main topic to lay the stage and provide you the lens from where we'll review all of these complex issues. So I'm sure many of you on the zoom today will recognize this figure. This is Willie Surtain. Jr born in Brooklyn is known as one of the most famous famous american bank robber during his 40 year career, he stole an estimated $2 million but that was in the early thirties and forties arrested a number of times and escape prison from a total of six times Just to put in relevance for you. His famous last escape include one in 1947 when he made a spectacular escape from home. Zberg county jail near philadelphia using one rail pistol, one dummy would pistol and guard uniforms truly fascinating. And in 1950 he was added to the FBI 10 most wanted list, arrested for the final time in 1952 and finally apprehended. He was asked by a reporter, why do you always rob Maness to which he replied, why that's where the money is. So now let's move to a completely different personality, William doc, one of the most prominent cardiologist of his era in the 19 thirties, forties and fifties considered Osler of the modern day because of its immense wisdom. Independent thought now also had a billion humor whose medical views treatment were sometimes at odds with accepted practices such as he was the one who championed back to chair movement within the 1st 48 hours of having an acute M. I. He's also well credited for the first description of early diastolic murmur when there is a severe stenosis of led. Something that's well described in the up to date section on murmurs edited by our own chief doctors agree. It's interesting to notice that in those days you may be diagnosing severe C. A. D. With a murmur. Now these are immense contributions and but many believe he also inadvertently pathway for a critical concept for our medical community moving forward that we can all learn even today. And the story goes like that. That on rounds as a visiting professor at hell. In 1960 he met a young Puerto Rican woman with an underdiagnosed liver disease and despite extensive series of tests suspecting the diagnosis of csto moses, he said, why don't you apply Seconds law in this particular patients perform a liver biopsy? The liver biopsy confirmed. Oh and the diagnosis. And so now looking at this. This would have been the end of the story Except there were also two Yale physicians on the teaching round robert, peter staff um here who ended up to become the chair of washoe president of the Brigham Women's Hospital in boston and paul Beeson who served as the chair of Emery and and Yale. And they were working on a phenomenon called fever of Unknown origin which has the whole medical profession baffled. Now a year later they published their paper on the fever of unexplained origin in which learning from from dr dark, they mentioned and recounted a certain law and said we are in with indebted to dr William doc for the term certain law. It recommends proceeding immediately to the diagnostic test, most likely to provide a diagnosis and deplore the diagnosis to carry out a battery of routine examination and conventional sequence in other words. To put things into perspective. I guess it reminds all of us based on our goals and what we were looking why waste time looking for things that are obscure or questionable instead of taking the path of least resistance and most likely to have a success and going directly to the source. I think this is a lesson somehow that has got lost over time in our medical community and probably needs another reminder and now with this the conceptual framework I think has significant relevance as we speak and deliberate best tragedies in realm of whatever you and I do in cardiology, but more so in prevention, where the foundation of our management depends upon one very simple yet most meaningful question, Who is at risk? What is your risk? Especially among those who have yet been declared without established cardiovascular disease? Of course, patients with established heart disease. There is little debate due to relatively elevated former genius risk above a certain level and hence claire degree of benefit with most intense treatment, but at the same time Extrapolating the same strategy of let's treat everyone is challenging within the primary prevention setting. Because the risk scale is extremely homogeneous. We're dealing with a large adult population. Maybe 90% of the adult population doesn't have established cardiovascular disease or even more. Not only we have to assess the options, but the intensities of management. This is not just statins and aspirin, but we also have finite resources and we have to think how best we can mobilize them and focus on who needed the most, not only at the individual level, but at the societal level. So how are we doing that? Well, there's not much to say here. Uh since the first time we were introduced with the term risk factors nearly 61 years ago by the legendary Framingham heart study, which was started in 1948 in response to the rapid emergence of the new phenomena cardiovascular disease since post world war two. Further spurred by the death of FDR. Our quest towards predicting the risk of heart disease had really relied on standard assessments of cholesterol blood pressure, lifestyle factors, health conditions such as diabetes, whether someone is at the risk to suffer a heart disease that form the basis of a restricted stat and allocation by national cholesterol education panel in 2002, Followed by full cohort equation in 2013, that is still the rule of the land. So in summary, it may not be unfair to suggest that from an innovation standpoint, our imagination has really stalled for the last 61 years and the only thing that we have been done is mainly selling our stakeholders the same product using the different quantities of the same ingredient by just shaking it differently. Now, the issue is not that we have to do things differently for the sake of it. But more importantly, ask ourselves how well these approaches have served us Now, my own personal experience in this place for the last two decades, I think we have truly struggled with the imprecise nature of the risk prediction model. While in the past, such as Framingham risk, we were challenged with underestimation of risk, Especially who would have benefited from established preventive therapies like statins and aspirin and fast forward to 2013, we have a risk model that is or estimates and asked to prescribe statins on a wide scale basis. As you can clearly see that even, I mean the usual who are candidates for statins with a 10 year risk of 7.5% the predicted risk is much less than than the observed. So many of us agonize or these efforts that I think are particularly speculative, resulting in significant loss of efforts, resources and missed opportunities. So as a result, I truly have held this belief for now almost 20 years that our risk assessment paradigms are prime from a dramatic makeover and the question in the richness of choices, where should we focus on? And I think so. We cannot do much wrong if we follow the certain rule, if the money resides in a specific area, then the path should be pursued immediately instead of several steps into a general algorithm that may lead to more confusion, uncertainty and speculation. Now This has a huge application in severe risk prediction because now over the last 50 years it is very clear that atras process though related to risk factors, is a very heterogeneous this condition with numerous unknown vulnerability and resilience factors. It's the true precursor of the actual complications which is Emma and strokes. And I think if we start focusing on that, it will take off our blinds and help us remove the shaft from the green. And among the choices of atherosclerosis assessment in the midst of all the chaos happening around us with risk scores nearly two decades ago. My dear friend colleague mentor arthur Ferguson put forward this new disruptive non contrast ct technology that's now widely available and as Samir pointed out, key to a point where majority it's about 55 $250. It's easy to perform that the texts calcified black as a surrogate of atherosclerosis and presence and burden the core culprit of future cardiovascular events and can potentially overcome the limitation of relying on the wide guesses based on modeling risk factors. Now, while in contemporary era I think so we have continued to celebrate Dr. Arthur Agatston remarkable contribution as we honored him at our symposium prevention symposium nearly 10 years at that, sorry 10 days ago. Uh if you take a look back his initial efforts who rather than getting a red carpet welcome was unceremoniously rejected by American Heart Association nearly 32 years ago for the same work that has now been among the most cited 30 years later and helped shape the guidelines. Clearly you can see that hindsight is 2020 but that said um let's come back to why we think Elson testing is the best option available for us Clearly now after 20 years, especially with the weight of evidence from multiple cohorts all across the world, most notably in us Mesa and Europe than Heinz next of Rico. We now know that for risk prediction there is no tool that is better. We have seen a graded and exponential increase in short and long term severe risk up 9-16 fold with higher calcium schools probably the only test that adds that can meaningfully discriminate risk above and beyond the time tested risk And more importantly results in meaningful re classification to impact a change almost about 25% in the journal population and 50% of you focused in the middle, risk. Not only is able to identify those who are at the highest risk I think that more importantly is a feature that truly distinct from other options is this novel concept of power of zero Um developed with um our server Mike Blaha way back in 2008 and nine when we were all residents and suggested that we can do even better and more reduced the noise but just focusing on absence of disease who are such a low risk that they can be afforded no downstream expensive CV testing and promoting the idea for the first time that the flexibility of preventive therapeutics now almost rejected by all major journals instantly as an idea not worthwhile to pursue. And this was the feedback I got at the young investigator award at the Northwestern symposium but only it was to the vision of Dr Fuster and Motorola that they simultaneously published these papers in Jack imaging now cited more than 1000 times and at the moment we had no idea that this would lead to not only a wonderful journey of discovery impact but also tremendous resistance from our community and as soon as these papers were published the criticism and the what about autism slowly started to trickle in mostly at national conferences debates in form of publications. I'm not sure we would have survived the onslaught if it would have happened in the current twitter era. The first two major concerns were who cares, especially if you have a high burden of risk factors, the chances of absence of calcium school is low and even if it's too unlikely to be associated with the low with the lower risk of M. I. And stroke. Fair criticism. However, in a data free data free world, we could only speculate, but I feel these criticism led to a new, whole new movement in trying to address this issue. The big issues, risk factors versus coronary artery calcium and truly no better example. To showcase this from the landmark paper from Seth martin who's at Hopkins ended his internal medicine residency at penn that there exists a significant Heh Trajan Itty with lipid abnormalities believed in that time and even today as something that is CV or afro equal in on the actual presence and burden of disease. You can see nearly 50% adults mean age 60 in neza with all the lipid parameters of normal, had no corny RV calcium score On the other extreme. This is zero by the way up to 42% of individuals with normal lipid parameters have some form of disease with one in five significant disease. This is clearly the finding surprise was surprising as why this is so emphasized and I can use this even as a coin toss, but more important when you look at the outcome, few critical findings were noted. The true risk is mainly mediated by the presence and burden of calcium irrespective of what the LDL abnormalities are. Those with the calcium score zero with the worst LDL. The risk was lower than somebody with normal LDL, but minimal amount of black and those were the highest amount of atherosclerosis were almost CBD equal. And if you think two year per year risk is CBD equal and they all afforded that. Now of course, a lot of what of autism came out. What about non HDL? You find the same thing. What what about the lipid particle size? You find the same thing? And somebody asked me yesterday, well what about the life of protein? A actually a recent paper published in the same thing. Clearly the story is the same. Even an elevated lipoprotein doesn't add anything for the risk factors. If you have a power of zero and it's not only about lipids, it doesn't matter how you slice or dice the pie of the risk factor profile. And you can look at inflammations and multiple risk factors and Framingham risk scores and people meeting criteria for polypill family history and aging. The answer is the same. Nearly one in three of these adults mean age around 60 have no coronary calcification and their three classified risk is well beyond the anticipated risk. Now with these insights in 2015, we try to address the challenges with the newly guidelines that showed what estimate risk Or crowding of the Statin Island and overall of substantial proportion of population asking the question, do I need to be committed to a lifelong therapy? And we sort out that whether calcium testing and especially the power of zero could overcome this challenging. And as shown in this 2015 paper, we reported that among the two thirds of adults who are already starting candidates, 1.5 have no arthroscopic disease and their actual risk was well below the threshold that as a society we would even consider statin and hence we proposed that the power of zero is a simple decision tool that can support statin decisions, especially when you're uncertain to identify the low risk, allowing us to focus on those who are likely to benefit. And though again, overall the concept was well received. There was again, a healthy dose of skepticism on this very concept of de risking and the thing that well, uh why can't we do it with more commonly available testing clinics, statins are cheap and effective. What's the point of upfront introduction of a test like calcium for 100 $25 there's still a lot of prevalent believe that somehow if you treat a lot of individuals who have a calcium score of zero, you can prevent a significant proportion of events. So going back again to the drawing board, we saw that in this case the power of zero is further strengthened by insects. That there is no other test that can de risk as compared to a calcium score of zero. From a societal perspective, it's cost effective to defer treatment in those patients. And more importantly, especially if the cost is less than 200 to submit 1 $25 is pretty good. And more importantly, even treating a lot of individuals for a long period of time, although not in our city. In our retrospective study, we didn't Joshua Michelle didn't find any yield For the effort of treating them. Only those with the presence of calcium and especially if it's created then 100 where you need to treat 11 individuals to prevent when one event. Now with most of the criticism addressed, the next piece was if the data is so good, why not adopted by the guidelines, I I can tell you in 2017 and 19 that was a little painful glow. And hence in early 2019, I decided to make a final plea to the upcoming guidelines that now with the emerging evidence and the critical piece of to risk assessment for treatment choices. We cannot hide behind the dogmatic pretext of lack of clinical trends. It's time, it's time to upgrade the role of calcium testing. Not as a screen test, but as a decision tool for those who have already been asked to commit to lifelong therapies and four years ago at H. A. We were all pleasantly surprised that the updated guide cholesterol management guidance acknowledged a lot of work that have shown you now and for the first time bringing into play this new phenomena of calcium score of zero. Now it was delightful to see the shift from the role of calcium testing from a screening test to a decision aid where it was recommended as we have been advocating since 2015 for as a decision aid for uncertain patients. And for the first time that suggesting that even if your estimated risk is high and the calcium score of zero, it is okay to be flexible with treatment choices. Now, if I I think that if we get a chance to reflect on this again, we may look at this as a critical point where as a society, we move the big ship in the right direction of C disease. While forces are traditionally estimation approaches Now furthermore, the concept was well received among thought leaders and I really attribute Roger Blumenthal for making the power of zero. Hashtag more famous during his guideline presentation at H as the best decision aid. Ron Blankstein the past sec T president thinks that it can cut the risk and half Donald Lloyd jones passed H. A. President Is using this as a reasonable justification to avoid delay treatment, legendary Scott. Brandy thinks that without calcium testing 40% of individuals may be over treating Harlan suggests that it suggests that if you don't need a statin and while booster being more blunt and suggesting to forget about statin in the calcium score of zero. Now with this guidelines coming up and feeling reassured that the story is done and also honored with the S. E. C. T. Prestigious Arthur Andersen award to the person who really just started the momentum. Almost 32 years back I was truly in the mindset of hanging my boots as far as the calcium investigations are concerned and to focus on the items that Samir pointed out like bigger issues on the role of big data optimizing are clear delivery process and their potential on social determinants of health in our clinical practice. That was up in front in my mind. But I can tell you this is where the power of zero honeymoon period ended. And the last three years have reminded me of this famous scenes from Star Wars where escaping from the imperial troops leah luke Skywalker han solo Chewbacca. They end up in this huge compactor. This too soon realized that the two walls are approaching each other slowly and steadily threatening to analyze them for the minutes. The situation is desperate and they're trying everything to stop the walls but nothing is making a difference. Eventually the resourceful droid R. Two D. Two gains access into the dead stars data, learn how to block the walls remotely and set the rebels free. Now this was my feeling and the question I'm sure you must be thinking what does this compactor scene from the 1977 classic have to do with the power of zero. So let me tell you what in the last three years, especially in social media at one end what we started seeing uh a small yet very local contrarian and lipid and risk factor centric minority that are still challenged with the terms of three decades of coronary artery calcium research and continue to advocate for legacy approaches to guide risk management and inform the treatment decisions. They think the power of zero is misleading because there are still gonna be few events unlike diamonds, calcium score is not forever shared decision. Working with the power of zero. Maybe again by asking people not to wear seat belts and the best one really is reserved to David Brown who who's made a huge fan following by suggesting nothing works equating it to coke zero. A good slogan now simultaneously. But in the opposite direction, some of our friends in the cardiovascular community were very much enthusiastic about the application of C. T. Angiogram. Currently a class one recommendation for assessment of Chessman. And by the way I'm a big fan of valuable research tool for advancing our understanding of biology of afro schools is where it's all about the non calcified plaque countering it's calcium role in any potential way. Even in primary care setting because it does not equate zero risk and dreading the possibility of perils of exclusive non calcified plaque that may be missed with the calcium score of zero. And as you can see that these issues are also raised with my colleagues and friends across the street at Baylor. That putting all of these things together that we need to treat everything and their non calcified black. It may be challenging for the younger individuals. And paradoxically, if we have flexible treat statin decisions, it may result in more events in those with the calcium score of zero. Now with these with so many red lines created or by our esteemed colleagues in the community for the last three years we felt it was time to roll our sleeves again I think for we needed to dare to be brave but address this, I ask you and I've continued to ask others that we can only achieve if we keep aside our sentimentality and focus more on the evidence generation. So let's start with the power of zero and the non elderly And even younger population. Clearly the issue is we did not have good data in the Prague mystification beyond 10 years. But that's what we use the ten-year risk. But of course for a 45 year or 50 years, we may be thinking beyond. So where is the data? We lack the data not anymore. This year we showed that the calcium score of zero lies even to a relatively younger population, age less than 55 in an extended year of 17.5 years, Less than 3% of individuals were at risk for a major cardiovascular events. Now, in perspective, if I ask you to refer back to the risk guide and say, where would you not even consider statin? The threshold is less than 5%. So clearly the risk is half even in an extended 17.5 years time period. And by the way, when you look at the risk factors, there are no differences when noted with almost any other major risk factor, especially this lip idem ian suggesting that we can be reissued with the long term risk. And by the way, this whole concept of moral hazard that if your calcium score of zero suddenly you will be on the street with a hamburger and a cigarette and a bottle of beer, It's not true. Most of these patients realizing that they don't have the disease are more interested in pursuing healthy lifestyle to maintain that. And by the way, the calcium testing is not a one time test, as you can clearly see up to a 15 year follow up that you need to repeat those tests in 3 to 5 years, especially depending upon what your risk profile is. Because if you maintain the calcium, your 15 year risk is This miserable 1.2. And if you develop atherosclerosis, which is not forever. And unlike any other test, this test is not forever. So bring them back in 3-5 years. That's really how the practical approaches works in our clinics. Now. Also while the power of zero is favorable on one end and ruling the risk, I think so we can push the envelope even further among those age, less than 40 years with not to rule out disease, but to find people who are at risk. And with a targeted approach where individuals have 3 to 4 risk factors, especially metabolic syndrome, family history, we can find premature atherosclerosis. We're not looking for a calcium greater than 100 by testing nearly one in three individuals allowing you to introduce interventions to change the lifelong trajectory. Of course, that's something that needs to be tested in well designed study. But I think based on the new insight is just a number and we can lower the bar for colony artery calcium testing even any younger individuals. Second now, while the guidelines in uh 2019 made a major move, taking three steps forward acknowledging see disease free disease. Um, I still think old habits are die hard and they took another two steps backward and suggesting well in circumstances where the statin decisions are uncertain why not? Additionally add a list of risk enhancing factors of almost any non traditional risk factors not encountered in Pc. And if President should be good enough to encourage stacking and use it even before the calcium testing. The issue is this is a totally evidence free zone and I am so indebted to dr Jaideep Patel at Hopkins and Mahmoud al Refi, our imaging cardiology, imaging fellow having a go at it. And what they found was not surprising at all because even among individuals, but already candidates were started with their 10 year risk of 7.5% at more. Even if they have any of these non traditional risk factors apart from maybe a which is a disease. Your 10 year risk is below almost at the word or lower than the threshold of 5%. And in fact, you may have a person who's 10 year risk is 10% and even has an elevated LP, literally triglycerides And CRP 40% of them will have a calcium score of zero and their ten-year risk is still below the 5% threshold. Your risk really depends upon whether you have a thrombosis and the burden what you have. So with all of this information, I truly have started to wonder why in 2021 and 2022, we are still debated on risk factors were sis calcium as predicting risk. I feel this is rather a classic definition of insanity of doing the same thing or and or again and thinking that we will have different results. And hence why not come back again to the certain principle and focus where the money is. And start with the colony articles in first. Now of course another red line is the issue of severe hippel epidemiologic, which I think it's a very heavily guarded notion and issue within our cardiology community and something that's not to be challenged. All the prior and current violence worldwide. Them a special risk status with an understanding that all should be treated aggressively. No need for actual imaging testing for management decision, how would like everything else? One need to question that does. Everyone with severe hippolyta demand. I'm not talking about familial genetic uh hypercholesterolemia but just severe happily demon clearly should they be treated equally? Clearly we're seeing in your practice and in my practice that many with elevated LDL has no calcium scores on multiple occasions and we have no guidance. There is no data on what their risk is. But thankfully a couple of years back in Mezza. Subsequently the guidelines have shown that even if you have a baseline LDL more than 1 91 in three of these individuals would have a calcium score of zero. And clearly the risk is well below around 3% 10 years and beyond. And clearly you can look from this data. Do you truly believe everyone with severe Happel epidemiology the same. So again, we see a space where the power of zero has overcome another hurdle. And I truly believe that in in the spirit of transparency we need to disclose and have our management discussions in in the light of these new findings. Okay, now pushing pushing the animal up even further. What about those who are genetically confirmed ex FH exposed to significantly elevated LDL since birth? What how many of those individuals in their forties and fifties or not aggressively treated would have a calcium score of zero? My guess is pretty low but in the same fashion we found that even a hetero that even hetero sickos if it is not a homogeneous disease and this matter analysis of nearly 1000 patients, we saw that 45% of these individuals, Middle Age individuals have a calcium score of zero. And working with my colleagues in Brazil in a cohort of familial hypoplastic anemia followed up to 10 years with a median follow up of five years. As you can clearly see if you have a calcium score of zero at least in the short term. In spite of the fact that your sub optimal LDL goals with no Pcs canine, you were at a pretty low risk. And this is by the way, not just one study. Now this is confirmed in larger cohorts in spain safe heart and other studies. So as a result, despite extensive resistance and fierce opposition, there is a growing consensus in the leading international efforts, collaborators that while we should continue to maximize status, the power of zero can help guide allocation of more expensive and advanced lipid lowering therapies, especially in developing countries. And it should be reserved for those who have early signs of atherosclerotic disease. This is part of our clinical practice and preventive cardiology. Of course this motion is heavily debated but doesn't mean it's a one time test. You bring them back every three years and if there is any change, you become more aggressive or intense now I think so we are all agnostic on the use of statins in these high risk group. I think so, everybody should be. It's cheap. It's effective. The side effects are not there, but who needs an LDL of 1 90 or 1 70. But I think these insights also will have treatment applications for more intense and expensive therapies like PCS canine, for example, in this severe hip all epidemic population. If you look at different criteria is whether you're going to have a more loose sources restrictive or very high risk. Clearly you can see that they are not the same. Almost about one third of these patients have a calcium score of zero and the 5 to 10 year risk is pretty on the lower side and it will cost a lot of money to treat them with PCSK nine. Almost about a million to $3 million to prevent one year one event in five years. Even if we believe that that it would do. But truly what you need to do is focus on people with a calcium greater than 100. Where your 5 to 10 year risk, five year risk is 15 to 20% of this is the group we need to focus. This is where the money is. We cannot have a gunshot approach. And by the way, the same applies for beyond LDL lowering therapies, whether it's aspirin, It is the emerging GLP one receptor agonist aiko safety in the tile or hypertrophy academia. Clearly, the summary is, if you have a calcium score of zero, your risk of events is very low. The benefit is going to be lower. You will need to treat a lot of individuals to have any meaningful information. Whereas if you focus in the one in three or one in four individuals who have a calcium greater than 100 you're gonna drive the highest yield again the certain principle. And in this regard, I completely agree with DR Madama That in 2020 making these decisions when you are faced. Should I go on a pcs can I what about aspirin? What about GLP one receptor agonist in a diabetic who doesn't have an established cardiovascular disease? I think that making these decisions without having insights from the coronary artery calcium testing is not, it is financially unwise and will result in suboptimal management. And I think these lessons have also substantially grown our understanding as we look forward towards the future on how to design the most optimal and efficient A randomized controlled trial for these emerging therapies by the way which none of them has been tested in the primary prevention settings. And we can do ourselves a favor by following the certain rule and focusing on individuals with the calcium greater than 100 or 400 if we have want to have a more efficient and cost effective trial, well described in a couple of papers and I agree with anne Marie, navarre and James llamas. That definitely is not a question, definitely. The coronary artery calcium testing is the secret source for affordable cardiovascular primary prevention trials in status. Now of course I would also like to touch the story about non calcified black. Um you know, as we look towards the future, I think we have to start deliberating beyond calcium testing especially with this emerging M. D. C. T. Technology with I. V. Contrast that goes a step further in providing a detailed architectural phenotype on the black civilization that can play a major role in our understanding, which is really limited on early initiation of atherosclerotic processes, especially the non calcified plaque and how it progresses and determines. I'm very bullish about the prospect. But at the same time, we have to realize that while Seti has been extensively studied within the symptomatic population mostly in the context of ruling out obstructive disease and not and being efficient. And that space are insects on the prevalence burden features, outcomes determinants in the primary prevention is limited and there is no investment from NIH so far to move in this direction which is mind blowing. So we Try to address decision 2015 and say we'll take The lead and we launched possibly the only existing population based cohort in the US recruiting nearly 2500 individuals trying to shed light on this issue in Miami and which finally in 2019 we finished up the recruitment. The results of the first results of this study was published earlier this year showing that even a younger population age 40 to 60 nearly half of them have some plaque on C. T. A. With a very diverse you know, typical expression as you can see here. But more importantly the key question is about 15 16%. About 100 and 50 patients in our study who have a calcium score of zero had exclusively non calcified Mainly as a streak in one single segment with less than thankfully less than 1% having any meaningful significant disease. Now the question whether this streak of black will have any meaningful prognostic value on top of the calcium testing. I'm hoping by the end of 2023 when we'll complete our five year outcomes will have some answers. How are you know it's always going to be a debate whether C. T. A. Will add prognostic information by an inch or a mile. When you account for calcium testing at least from the literature. It's been suggested in well designed cohorts such as the scott heart study which was mainly for the symptomatic individuals that once calcium burden is accounted, there is little prognostic value of worse black obstructive disease. Even the risk was it's truly about the burden. And on the other hand, in a long term study up to 13 years where we usually see that the calcium zeroes out obstructive disease by 99.5% 6 to 10% still have non calcified plaque. You follow them almost all up to all the 13 years, they may not be at risk for a major cardiovascular events. And again, questioning the utility of a test which is expensive needs contrast, not widely available but should it be a path and parcel of risk assessment and management, it will need to create a lot of the bars to get there. But I as far as understanding atherosclerosis progression and the social and environmental and biological determines there's no better modality for that. So clearly the future for atherosclerosis. Calling atherosclerosis imaging is right. So in trying to summarize, um I think it's it's humble beginning in 2009 while For the last 13 years, power of zero has been called. Many things like a mere slogan Blind Spot Pandora box fallacy. I must say despite all of this. It has stood up to stood up face the test of times garnered international momentum has impacted a major shift in the primary prevention diamonds shaped our view on atherosclerosis process with this understanding that there is a group which is truly resilient where we used to think they had to have disease and have no disease and tend to do pretty well and at the same time as a marker of vulnerability and we have also learned how best to deploy it for rapid diagnosis and management of early cardiovascular disease. And based on what I have seen apart from the stacking news which I believe as far as staffing decision is concerned, the role of calcium testing is now extremely well established guideline endorsed ready for prime time if I have to bet it still has some additional applications And my top five predictions are taking a cue from the certain rules. Clearly what we have seen that you can slice and dice the risk factor by anything you can continue to add as much it is. If the question is what is your risk and that's going to drive management, then we have to start with the calcium test was second while not reflected in the prior guidelines. Now we have also learned that it has a role in higher risk individuals such as diabetes severely elevated LDL. Even in familial hypercholesterolemia because not everyone at high risk is the same and in this era of position medicine we cannot treat or think about them as the same. Who needs aspirin. Who needs a GLP one who needs a P. C. S. K. Nine. There is no way that the traditional. Guestimation approaches will help us there and in the future we have to understand whether these therapies are gonna be applicable and we can learn lessons from an oncology colleagues on the principle of double enrichment where you are taking visuals with high risk exclude those who are low risk such as the calcium score of zero. Only roll with the calcium greater than 100 or 400 test the benefits of those therapies in an effective and cost effective man I think that age is just a number and now we have enough data that we can truly replicate some of our retrospective finding into perspective whether analog rhythm can identify the high risk where my goal is not to find calcium 100 but just any calcium in a 35 year old with all of these interventions coming in to change the trajectory of the disease and exciting space. And of course C. T. A. Has the most tremendous potential in unlocking the black biology. Its role is going to be extremely promising. There's no reason that calcium testing and CTE cannot go hand in hand and as we have to wait for this to happen. My final recommendation is that we can do ourselves a huge favor and follow the certain principles focus where the money is keep things simple see disease treat disease rid of the disease more intense than treatment therapy though, this concept is getting traction is still not widely accepted. But I think that after being ridiculous for almost a decade, I think we are in this second phase of fierce resistance as I've shown you. But at the same time I'm optimistic that not too far from now, it will become a widely accepted standard of care. But even with this 13 years of extensive data of reassurance and helping us understand who to manage and how to manage for those who still remain unconvinced. I just want to share some humor. I think in the message of transparency and spirit of disclosing to the patient. At least we should let our patients know you have a rare condition called good health. Frankly, I'm not sure how to treat it. And obviously at least there's nothing wrong for the next 5-10 years with you. But I think a little statin or aggressive management will make me feel much better. So Samira, I leave it here again. Thank you so much for the invitation. I hope uh, this stimulated a lot of thoughts and we have enough time for a more deliberative discussion appreciated graham, Fantastic talk. Thank you very much. And you know, I find this topic very fascinating. Even as an interventional cardiologist, I'm gonna start just with this basic notion of what we've all been taught, which is plaque starts as a lipid streak. It starts as lipid deposition. It's a soft lipid rich plaques but it takes time name for that plaque to divide. Okay, all specifications enough and see and they can this deposition or pick it up on an E. B. T. T. Until later in your life. Your forties, fifties, sixties. So how do you differentiate this and write with a coronary calcium score? Right. So similar. I'm sorry. I think you were cutting off a bit. I think so. Your whole notion is of course non calcified black starts earlier. Are we at the stage of missing? Maybe it's too late. So, you know clearly this is about uncertainties and trade offs. Um what we have started to learn and we have done some work first of all challenging this notion to is that with higher calcium scores, maybe you're gonna have more stable plaque and lower calcium scores. You're not going to have it. And the non calcified plaque is everything by the way, let's start with this. Not every non calcified plaque is lipid rich, right? It's fibrous. It could be anything that is a huge overlap. Unless and until you have a lower traditional black that's the movement. Most of the plaques with the Calcium score of zero are literally in our study in one segment in a streak. Now what does that mean? Who knows? That's number two at some point the risk has to be meaningful. We develop plaques in our iota all the time in our lower extremity. We don't have em eyes or of the M. S. It's an I treated process clearly it's about the burden at least in the short term. And calcium is a great surrogate. Which the scott heart study has shown. If you take into account calcium schools even your one durable plaque it doesn't really add up. We have studies now up to 15 years, 17.5 years in Mesa And 13 years in UK. That shows if you have a calcium score of zero your 17 year is well protected. Now like any test it's not a one like Samir you came in and your early 40 and I did a calcium score. And that said if you have risk factors of course lifestyle management and again if you understand and of course why not? But I'm gonna bring you back in 3-5 years for a repeat calcium. Now of course if you transition don't transition clearly for the next 15 years you're still at low risk and most of the people don't we still see 60 years old hipaa epidemics of it. We have no calcification. And then if you transition we start the aggression aggressive treatment now F. C. T. A. Was widely available you didn't need an I. V. I don't think so radiation is an issue and cost will not be an issue. And I can tell you that taking about 40 to 50 minutes to do one test and needing an expertise and ivy in the cost. It will not become a mainstream desk. Yeah, for severe hypoglycemic. Maybe some diabetic, maybe some point the future is right. So again, what's the option? The option is either you treat all which have clearly shown you that it's the most imprecise manner in what we do or we shift to something like a calcium score of zero. Is it perfect? No. Is there anything better than it? No. So I think so until we find some ground that shows this approach is better than a calcium testing. I feel that that $125 spend at your institution out of pocket will go a long way in helping your patient understand where there are what they need and you to treat them um precisely rather than having a gunshot approach. Samir do you mind if I ask a question? I'm sorry I joined late. That's a wonderful talk. Thank you so much. I uh had used calcium scores not infrequently but my question to you is what if you have a carotid ultrasound that shows plaque, What if you have other? I mean is that just as good? So 22 great points. One is you know I I personally believe if adding a few $50 like in our institution and you get a calcium score 450 you have another 50. You get the corroded a more comprehensive is more important. Now the question is is that important? Of course independently. Now I wish erotic black would have had more prognostic value because it's an office based that we should apply that unfortunately in mesa and high stakes stuff in any study didn't panel Now the question is of course there's gonna be a few patients with the calcium score of zero who don't have black and it means that they have published the study And yeah it does add a relative risk. But you know you may need to scan more than 1500 people to identify one who would benefit. So in essence yeah a comprehensive analysis is better especially in the young. I would advise that why not? If you have black early process that means maybe early initiation of simple preventive therapies more closer follow up and even in people who are unsure but if it's about choosing one versus the other I think so the calcium scores prime and the added value of getting started if any is extremely minimal. But I agree with another $50, why not? And being more comprehensive is better than just doing a calcium score. I was sort of thinking actually if you have somebody's gotta credit ultrasound it was done and it shows plaque, right? Does the coronary calcium score add to that risk assessment or just it does isn't enough to treat you know if you had a chaotic black and if you have a calcium score of zero significantly down regulated risk. If you have a high calcium wherever you are significantly up regulated the risk. For for example if the statin decision may not be a huge issue, I would just move with the critic plaque. But if you're thinking about aspen uh if this is a severely happy epidemic and you've gotten their LDL to 100 or 90 and you say okay, do I need a P. C. S. K. Nine? And if this is a diabetic with the B. M. I. Of 30 and say well this patient benefit with the GLP one receptor agonist or the triglycerides in a 1 40 range in spite of the stat and that's where the calcium testing will kick in because if you don't have a calcium greater than 100 I think so you can be more flexible and just focus on status. Thank you. There's one question there you saw, which I think is an interesting question. So it's a good test. I think a lot of people would agree you presented some wonderful evidence. That fact. Why can't we get insurance companies to pay for this thing? Uh You know it's a long story. Uh You know my my understanding is two for one is of course, you know the calcium testing really came out one as in the 19 nineties we have no idea what to do with it. So it was more around the competitor for cannot rule obstructive disease Of course fierce resistance by as nick and other societies never made it happen Then. It was considered as a screening tool really that I need to screen people to find people who need to treat. And of course you need a clinical trial to show that that benefits colonoscopies and everything thankfully. And now we have a clinical trial in Dan canvas in Denmark that showed that treating a lot of men and calcium testing and leading them to aspen and start an initiation has a mortality benefits age 65-70. I think some of their data will help. But post-2013 it moved to a decision really. The calcium testing was mainly for individuals where you're deciding whether you need statins or not. I think we haven't found the real support from the societies where apart from preventive cardiologist like a C. C. T. Where I think they're competing more with the C. T. A. And trying to make that more of prominent. So we don't have the advocacy. I truly believe that it's an advocacy issue. Now what happened harvey what happens is Even if the calcium testing now becomes paid by insurance which happening in fuel. Honestly the out of pocket cost is still going to be around $5200. So you know, it's kind of a double edged sword. There's a lot of political financial I would say challenges that have happened. I think so eventually we will get there. Now the question is would the out of pocket costs go up is yet to be determined. Yeah. I think the only for patients it becomes more of a, well if it's not paid for by insurance is this test really all that useful? It's really more psychology. I agree about the financial side but it's just when they see well insurance pays for it. That's probably a good test. I can. No no. True true. I agree. I agree. We we still have a long way to go there. Samir I'm wishing for you. You know a lot of patients get cT scans of their chest and recently at least locally a lot of the ct scans will report. You know you have a nodule of this size, here's what we recommend and we're starting to see comments on coronary calcification scene but it doesn't go beyond that. Is there a way or is there a push to quantify and actually obtain a score on all these cT scans? It seems like almost everyone gets a cat scan at some point in their life anyways. The great point I think so extremely under utilized resource. There is definitely a lot of momentum in this space from S. C. C. T. And many other folks like David Maron and other at stanford. So that two parts one is qualitative reporting. You have disease mild, moderate severe. It has shown to be very accurate. Should it be reported. Yes. Absolutely it should be reported. So that's number one, number two. Once it's reported, of course each institution has to start having own internal processes and how to react on this. Whether that should trigger at least a prevention follow up with a preventive cardiologist, cardiologist or even primary care. So again it's kind of like saying okay you are addressed or you have CBD now what to do it. So it has to be reported. It has to be disseminated and there should be some processes falling in. The other thing is automatic. Ized AI algorithms are now working pretty well that can tap into your bags and really go through all the images and identify. And of course there was a paper in nature digital health by david marin and their group that should pretty accurate and not only reporting. And by the way I'm sure at hee they may be presenting some data on this and how automatic detection of black putting in a report, sending a message to the primary care and to the patient at the same time how it's significantly enhanced utilization of statin and a population who were not on that but had the chest city. So absolutely this is an area that we need to pursue. And if you have a calcification on a non gated city you don't need a calcium school. Are you able to actually get an Agatston score on any ct scan so you can get an approximation. So the ai program that the paper was published was very accurate almost 90% or more. But again, if it says it's so we're more than your calcium, maybe 100 and 52 or 90 or 70 it's kind of still better than. And if the idea is early initiation of prevention, I'm saying you see disease at least start a statin, why do we have to wait till the calcium has to be 100? Because it baffles me from a society recommendation when they say, well, oh my God, if your LDL is like 1 29 lifelong commitment. But if your calcium score is 50 you can think about it. And I'm saying this guy has the disease? The process has already started much higher risk. So you're okay for us to wait. But this guy has no disease and you want us to be aggressive. I think the guidance needs to be reformed at some point. So I don't blame the 2019. I really I give them credit for taking that first big step. But I think so as we start moving along, any calcification is going to be well let's get the start. And and if the idea is to reduce risk. All right. Um do you have time for one or two more questions coming through here. Um So based on the evidence you presented, what steps, what subset of primary prevention patients with a score of zero would benefit from a statin. Look as I said, there is no such thing as a zero risk, right? You know, our biggest challenge or pushback has been that the power of zero means zero risk. Of course this was just a mere fun hashtag that popped up and it really got stuck. So, you know, even in 2009 we showed that people with diabetes smokers, so we're hipaa lipid right? With the calcium score of zero are relatively at a high risk. So again, it's very important to decipher the relative and absolute risk. If you have a calcium score of zero, you got an absolute risk is pretty low like that 0.5%, 10 year risk of mortality and things. And if your risk goes from .5 21, that's two for risk. But that it's not the same as going from 5% to 10%. Now the choice is there, you can start them on a treatment or if they have a calcium score of zero. So there are two options. If you believe this is once in a lifetime test For a 45 or 50 year old and I'm never gonna repeat it, then diabetics, maybe smokers absolutely severe epidemic one. But if you believe in that this is a night traded process and some people will move to positive and that's the way the risk and some people will continue and you want to bring them back in 3-5 years. And I think so you can have the flexibility. But in 2022 I think the issue is not about only starting a status. What about high notes that Do you want to achieve your LDL less than 70. What about if you started someone on therapy? Where do you need to go? What about aspen? So I'm just saying that is it like you're going to just start a statin and forget. What about if that patient still have progression of disease and in 10 years as a calcium of 120. So this notion of calcium testing once we need to get rid, bring them back in 3-5 years. Especially if they have a calcium score of zero to help you define your management. But again, this is more of a shared decision making. If a patient wants to stand and why not? But we need to disclose whether what the actual benefit is going to be there in the next 5 to 10 years which we have seen is minimal. If any. Does the location of the calcium make a difference in prognostication? So if it's in the proximal led versus the distal. Right? So the key thing is as you know, unfortunately it's not a true it's a surrogate. Yeah. You may have a plaque, minimal plaque but that may be cyanotic versus not. But it's a surrogate of the total. So what we have seen is of course, once you don't have the black, that's a separate story. Once you have it, it's how many vessels, how distributed it is And how many plaques can further refine, especially if you have a calcium 12 amendments. So in individuals, if you have a calcium score of 60 in just one local spot in led, maybe proximity or distance. So people have looked at the proximal and district, we didn't find much differences. But if you have the same amount of plaque, let's say in three vessels and rather than two plaques, you have seven plaques. The risk significantly elevates. So in our practice we have a very comprehensive approach. We're trying to promote that into the folks that you should look at the entire picture. But you know, I mean the problem is we're still having the first hurdle problem and people to accept and get start getting a calcium score. So hopefully in the near future when it becomes more mainstream will have more ability even with AI and everything to re identify the distribution number of blacks. The densities that will help us refine the risk even further. But I think so. We still have to cross the first hurdle. Harvey. I have one more question. But do you have any that um that you want to ask, I know we're getting late in the hour. I think you're muted. Harvey still you're muted. But I guess in the 11 question for me and that patients often ask about repeating their scan and what a score means. You know they have this mentality that if my scores I I go on a statin my score should come down to um how do you interpret longitudinal studies and a patient and what does the danger and score mean to you? It's always a question that comes up. You know and you know it's how we have done things um your is high it's gonna come down your blood pressure that high we're gonna manage it. And so we've always done that now. Think about that that once someone presents with an M. I. Nobody asked that question right So I need to see what the progression of my plaque is. So I explained to them that you know this is I would say an advance process that has happened. This is an indicator of your disease burden and risk. We are unable to tell whether the black features will change. Although we know from extensive studies by these proven therapies the black will stable. The non calcified black will come down and the risk of a rupture and complications will be less. Now if you're interested in truly seeing what is happening then maybe it's time to pay out of pocket for a C. T. Look some people want are ready to pay 405 100,000 whatever dollars and that's fine. But you have to disclose very clearly that this is not going to tell us that. And the only that's why I tend to repeat calcium. Only in those with the calcium score of zero who we choose to have flexible therapies. Now with ai and certain we're trying certain groups are trying to see whether based on the non contrast, whether it can help us identify some of the features that you're going to get on the contrast. I think so. It's going to be a heavy lifting. It's really not going to happen. So the first this is kind of my feedback to the patients where very candidly disclosing them what a calcium vest is, how it's not going to be any of any help as far as looking at the progression of the disease and we can choose C. T. A. And if they have more symptoms at some point then you may want to pursue some of the functional testing. But that's it. Alright fantastic. I think unfortunately harvey are you still having technical issues on your end? No I got it working again. Thank you. Uh Actually it was a wonderful wonderful talk and very instructive. Um I think I think your your your your approach was is exciting and and the facts and and and the data. You present the support and is wonderful and I think all the participants learned a lot and I think we could go on for another hour with questions that's clear that there is a whole new area in the symptomatic patients if you ever want to learn or have a more discussion that's even more controversial. Would love to talk about that at some point. But we look forward to having you back for that talk. Thank you so much for taking your time. Very much appreciated. Samir. Thank you linda. Thank you. Thank you everyone linda. Thank you Every for everything. Take care. Bye bye. Thank you.