 Good morning. I'd like to thank the organizing committee for inviting me to speak to you today. I will be speaking to you about the use of coronary artery calcium score to determine the benefit of aspirin therapy. As we've seen over the past couple of decades, technology has incorporated itself in every aspect of our management of patients. We've gone from only using clinical history and physical exam to an example, comical example, is this gentleman who his physician is telling him that he has a sensor in place that detects his cholesterol and when it's too high it'll lock the kitchen door and turn on his treadmill. A little background on the incorporation of calcium score for determining aspirin therapy is that since 2018 there's been three landmark randomized control trials that have addressed the use of aspirin for primary prevention and aspirin has not fared so well. There's been two large meta-analysis and the findings have been that there's limited benefit of low dose aspirin for the primary prevention of ASCVD events which on average is offset by an increased risk of bleeding particularly in higher bleeding groups. Increased use of statins, better blood pressure control, treatment of diabetes, may have blunted the benefits of aspirin therapy. The 2019 American College of Cardiology and American Heart Association guidelines for primary prevention has decreased the classification for as a recommendation for the use of aspirin from a class 1 to a class 2b recommendation because of the availability of this data. And to summarize these trials briefly, I mentioned here the trials of aspirin because it's led to a decrease use of aspirin. At the Esprit trial took 19,000 elderly patients who did not have atherosclerotic cardiovascular disease at baseline. A median age was 74 years of age and this study showed that low dose aspirin versus placebo did not prolong disability-free survival or reduce the incidence of the composite secondary cardiovascular endpoints over a four-and-a-half-year period. It also led to a significantly higher rate of major hemorrhagic events in the aspirin arm. The arrived trial took 12,500 primary prevention participants who did not have diabetes. It included men over the age of 55 and women over the age of 60 who were at moderate cardiovascular risk. Low dose aspirin again did not significantly reduce the incidence of the primary study endpoint was a composite of cardiovascular death, MI, unstable angina stroke, or TIA. It led to a two-fold increase in gastrointestinal bleeding events, most of which were described as mild. The ascends study took 15,480 diabetics without known atherosclerotic cardiovascular disease. The mean age was 63. Low dose aspirin in this group of patients did reduce the risk of the composite endpoint, which included myocardial infarction stroke, TIA, or death from a vascular cause by 12 percent. However, this benefit was offset by an increase of 29 percent in the risk of first major bleeding events. These three studies were incorporated into a meta-analysis in 2019, which added 10 prior trials comparing low dose aspirin with placebo individuals who did not have a history of MI or stroke. The findings of this trial showed a 11 percent relative risk reduction, therefore a modest reduction in the composite cardiovascular outcome of cardiac mortality, MI, and stroke. However, it was offset by a 43 percent relative risk increase in major bleeding events. I mentioned this study because it is important when we look at the studies using calcium score, which applied these benefits and risks to their populations. So if we look at the primary prevention guidelines, low dose aspirin might be considered for primary prevention in patients who are between the ages of 40 to 70 years of age, who are at higher ASCVD risk, which is not absolutely defined in the guideline, but who are not at increased risk of bleeding. Patients who are above the age of 70, it receives a class III indication for harm, more than benefit, and in any patient who has an increased bleeding risk, aspirin has a class III indication to avoid its use. So calcium score has been advocated as a tool to capture subclinical atherosclerosis and potentially affect how we utilize primary prevention therapies. CT coronary calcium score is a relatively cheap modality. You can get a test anywhere from 90 to 150 dollars, which is roughly what you'd pay for a generic statin for 18 months. The dose of radiation is somewhere around 0.89 millisieverts, with modern tech jolly probably a little bit lower than that, and this is using as a frame of reference that the average person receives about three millisieverts of radiation from ambient radiation. As you can see to the left, the calcium score can very easily detect calcium deposits in the coronary, in the frame to the left, you see the structure in the middle is the heart, and there's no coronary calcium, and as you go from right and then left to right on the bottom, you see a progressive increase in calcium deposits. We know from the multi-ethnic study of atherosclerosis that these calcium studies, these calcium tests, which were evaluated at baseline in patients and looked at prospectively, were very clearly linked to an increase in atherosclerotic cardiovascular events. Patients who had a calcium score of zero had a much lower risk. Patients with calcium scores of over 300 had a seven-fold increase in risk of atherosclerotic cardiovascular events at five years. Furthermore, this modality has been used to assess the potential benefit of statin therapy. This study, which was performed in 13,000 healthy volunteers without pre-existing cardiovascular disease at Walter Reed, who had undergone baseline coronary calcium scores, they were matched to patients who were on statin therapy at the initiation of the study, were matched to controls not on statin therapy. What you can see from left to right is that patients with a calcium score of zero, there's no difference in the curves and the Kaplan-Meier curves over time between statin and non-statin treated patients. As the calcium score increases above zero, the curves start to separate, and then clearly above a calcium score of 100, there is a significant advantage to being on statin therapy as far as risk reduction with the number needed to treat of 12 patients to reduce one event for patients who receive statin therapy versus those who don't. Because of this, the primary prevention guidelines have incorporated coronary calcium as a tool to help clinicians in decision making. Patients with a calcium score of zero are thought to be at very low risk and it is reasonable to withhold statin therapy and reassess it five to ten years, particularly if there's the absence of other enhancing factors such as diabetes, premature atherosclerotic disease, and the family and tobacco use. With these studies as a background, there have been several studies that have looked at the use of calcium scoring to further define what patients may be at more risk with aspirin therapy and which patients may benefit. This study from the Dallas Heart Study, which is a large prospective population-based multi-ethnic study in the Dallas-Fort Worth area, sought to examine this association. The patients in the study were free from atherosclerotic cardiovascular disease and were not taking aspirin at baseline. They found 2,100 patients in their cohort. The average age was 44 years of age. There was a high prevalence of women in this study, 57 percent, and 47 percent of patients were black. They followed patients for a median of 12 years. In the study, there were about 116 major bleeding events, 123 atherosclerotic cardiovascular events, and they did an excellent job of capturing events through the Dallas-Fort Worth Hospital Council data initiative database. Of the bleeding events, 70 percent were gastrointestinal, 16 percent were intracerebral. Of those total events, 21 percent were fatal. They utilized the meta-analysis that we discussed previously to apply the relative risk reduction of 11 percent and relative risk increase of 42 percent to the population at different risk profiles from the pool cohort equations and from calcium score. One finding that is of interest is that on the figure to the right, we see that as calcium scores increase, with a calcium score of zero as the line in black and a calcium score of 100 or more is in blue, there is a progressive and expected increase in events, as we see in the Mesa cohort. But interestingly to the left, you see major bleeding events which also seem to track with increased calcium scores. This increase was not as apparent after multivariate analysis, but it was the trend still existed showing that increased calcium score, increased vascular disease frequently tracks with increased bleeding risk. If we look at the risk of atherosclerotic events, in other words, the estimated increasing bleeding event rate versus the reduction in atherosclerotic cardiovascular events on the left upper quadrant, you see that it doesn't seem that for the population as a whole, there's any point at which the risk of ischemic events is lower than the risk of major bleeding events. If we start looking at to the right and then from left to right on the bottom, we see that as the estimated 10-year ASTVD risk is calculated by the pull-court equations, patients with an ASTVD risk of more than 20% do have a benefit of reduction in atherosclerotic events that's higher than the increase in bleeding events. If we look at this data in a little bit more granular fashion, if we look at the patients with lower bleeding risk of the population, we see in the left upper corner that patients with a calcium score for the total population have an improvement in outcomes that's better than the increase in risk when calcium scores are above 100. And this is particularly true in patients who have, as seen in the lower corner, in patients with an ASTVD risk of over 5% who have a calcium score of over 100. Those patients and those with ASTVD scores of over 20% derive a benefit that's higher than the risk of bleeding. Mind you, the numbers of bleeding events were very low in the over 20% arm, so it makes it difficult to clearly assess this trend in this population. So it's estimated that in these lower risk bleeding patients, you have a 1.6% reduction in the 10-year of expected ASTVD events versus a 0.9% increase in bleeding in patients who have a greater than a 5% ASTVD risk at 10 years. How about in those patients that have a higher bleeding risk? Well here what we see is that in the total group and regardless of ASTVD score and regardless of calcium score, patients who receive aspirin and have a higher bleeding risk in primary prevention seem to have more bleeding risk always than reduction in event rates, suggesting that in patients with higher bleeding risk, aspirin generally should be avoided. In this group of patients, a 0.5% reduction in the 10-year expected absolute ASTVD risk with aspirin was mitigated by a 1.2% increase, absolute increase in bleeding risk. Who is not at low risk of bleeding? Well for this study, they looked at, they classified patients as being at not low risk if they were on non-steroidals, on corticosteroids, anticoagulants, SSRIs, PPIs, antiplatelet agents, or if they had a history of peptic ulcer disease cirrhosis, cancer, CKD, thrombocytopenia, or uncontrolled hypertension. There were several limitations for the study including the low risk population, the patient's 10-year AASCVD event rate in some of the low group bleeding risk patients was as low as 0.5%. So it may have been a suboptimal setting to assess the potential benefits of aspirin, which we generally consider in higher AASCVD risk patients. The second study I will comment on is the MESA sub-study. The MESA sub-study looked at calcium and the name of the study is not the MESA sub-study but just to denote the population looked at. The study aimed to assess the value of calcium for guiding aspirin allocation in primary prevention. They used the 2019 aspirin meta-analysis data to apply risk to the different populations of AASCVD risk divided in less than 5, 5 to 20 and more than 20% like in the previous study. They also defined calcium score groups as 0, 1 to 99 and over 100 in an exploratory analysis. They looked at calcium scores of over 400. The outcome of interest in this study were CVD events which were composed of fatal and non-fatal MI, non-fatal and non-fatal stroke, other CVD death and major bleeding events which were bleeding events that they could capture as hospitalization. They excluded patients in this study who had at baseline high bleeding risk so patients with CKD, patients with severe liver disease who are on anticoagulant drugs or who had uncontrolled hypertension were excluded in the analysis. Of the total MESA population which is 6,814 patients, 1,200 were excluded due to baseline aspirin therapy, 1,200 were excluded who were over the age of 70 and patients who had high bleeding risk were 410. So for the total population there were 3,540 patients with a mean age of 56 years of age, 55% were women. Median estimated 10-year ASCVD risk was 4.1%. There were 10% patients on statin therapy and what you see is with higher baseline calcium you also saw higher ASCVD risk and that's what we see in the left side panel in orange. As you go from a higher calcium score from 0 to 1 to 99 to over 100 you see a graded increase in the number of patients or percentage of patients that have a moderate or high risk. To the right we see the assessment of calcium score according to baseline ASCVD risk and I will highlight that almost 20% of patients had a calcium score that was over 100 in the low and moderate risk patients. I will also highlight that in the patients with the highest ASCVD risk the over 20% almost 40% had a calcium score of 40 but a significant number of patients 32% had calcium scores of 0 which by outcomes assessment would be a population we would consider maybe withholding aspirin therapy for because of a lower risk. When we look at the number needed to treat with low dose aspirin for five years to prevent one CVD event and plot that with the number needed to harm to cause a major bleeding event by baseline coronary already calcium score we see that it's only and I'll highlight that the red line denotes the number needed to harm in that group. The number needed to harm becomes favorable on when the when the calcium score is over 100 in light green where you see that the number needed to harm is 518 compared to 140 number needed to treat to prevent one event and in darker green the exploratory analysis of look appears even more favorable although they didn't have bleeding events to account and and make an assessment of harm the number needed to treat is more acceptable in that group of patients and to the right it's the same data but separating by sex and you can see that in patients who have calcium score of more than 100 again in light green the number needed to treat is lower than the number needed to harm. Interestingly ASCVD group separation did not seem to clearly separate for benefit with regards to number needed to treat versus number needed to harm if you look at it in blue which is the total group of patients with ASCVD risk of less than 5 5 to 20 and more than 20 the number needed to harm is barely beneficial in the group as a whole in patients above the the above an ASCVD risk of 20 percent 10 year risk of 20 percent it's not until you look at the calcium scores that are higher namely in the light green and dark green where the number needed to treat is lower than the number needed to harm which is the line in red so this suggests again that calcium score is a valuable tool to separate the patients who may derive benefit from aspirin and whose benefit is is higher than the potential harm of aspirin major bleeding again these studies this study equates bleeding risk and ASCVD risk and for a patient for an individual patient and the physician they may not see those as equal in the patient and so that's important in discussion you have with with the patient regarding the risk benefit of treatment so you need to consider the totality of available evidence for CD risk inclusive or appropriate of risk enhancing features such as strong family history of premature MI if you can't control the lipids the blood pressure of the glucose to targets those patients may be at higher risk and aspirin therapy may be particularly beneficial in them and obviously as we mentioned significant elevations in coronary calcium you also need to incorporate bleeding risk so older patients patients on concomitant any thrombotic therapy patients with history of GI bleed CKD thrombocytopenia or drugs that may affect anticoagulation should be incorporated in your decision making I want to mention this specific case because I I like to show it it illustrates the importance of follow-up and in patients with calcium scores of zero this 53 year old male with hypertension whose mother had four vessel cabbage at age 56 and did not want to take statin therapy with a modestly increased LDL at 94 and a low mildly decreased HDL we decided to do a calcium score as my thoughts were that it would be elevated and we would be able to start therapy his ASCVD risk would put him in a low risk score at 4.9 at five years we repeated the scan and just to follow up and assess and his calcium score had gone up to 20 224 his ASCVD score would have qualified him for statin therapy and were super statin was started 12 about 15% of patients will become positive after a zero calcium score at four years and at five years about a quarter of patients will have a positive calcium score as seen in the Mesa population so in conclusion in the primary prevention of atherosclerotic cardiovascular events individuals considered potentially good candidates for low dose aspirin therapy namely patients less than 70 years of age with no high bleeding risk features who are believed to be at higher atherosclerotic risk clinicians may want to quantify the calcium scores to guide personalized aspirin allocation individuals with calcium scores of over 100 and in particular patients with calcium scores over 400 may be good candidates for aspirin therapy for primary prevention although the net expected benefit will likely be modest in the presence of coronary coronary artery calcium scores of zero the bleeding risk is greater than the potential benefit and aspirin for primary prevention should be avoided so with this I conclude I'd like to thank the organizing committee for giving me the opportunity to speak with you thank you very much