Second Chances: Real Life Challenges in Secondary Prevention of ASCVD

 

Hi, I'm Nicole. It's a privilege to be with you to discuss second chances and real life challenges in secondary prevention. So these are cases that we're going to discuss that I've encountered over the last few decades as a nurse practitioner and a clinical lipid specialist. These are my disclosures. For this discussion, I would like for us to first identify patients with a history of cardiovascular disease who are at increased risk for recurrent events. We'll do this by looking at some case studies of some very high risk patients, and we'll discuss some guideline recommendations for these type of patients and review currently available therapies from cardiovascular outcome trials that have demonstrated benefit to reduce recurrent events. And along the way we'll address lifestyle, which is important to consider with our patients. So atherosclerotic cardiovascular disease ASCVD is characterized by atherosclerotic plaque. Now that plaque may be obstructive or non obstructive and it's chronic. Once it's there, it really doesn't go away. And it tends to be progressive and dynamic. It can change over time. Now, even though it's dynamic, there may be long periods where it's silent, where it's just chronic and stable, but there may be times when it progresses into acute coronary syndrome. Now we know that atherosclerotic cardiovascular disease is caused as a result of oxidation, inflammation and endothelial dysfunction. And this is a result or it's driven by risk factors, especially if risk factors are uncontrolled. I like this slide from the European Society of Cardiology that shows that natural history of chronic coronary artery syndromes and we see here that on the Y axis is cardiac risk of death or MI over over time. And cardiovascular disease starts as in the subclinical phase, and it can progress into one of three trajectories. So at most the trajectory is determined based off the risk. And if the patient's been adequately or appropriately revascularized and optimal medical therapy. So if revascularization has been appropriate, atherosclerosis can stay in that chronic, stable condition or it can progress into an acute coronary syndrome requiring revascularization. The chief concern are those patients who are very high risk, who have acute coronary syndrome, and they're at risk for recurrent events, especially if risk factors haven't been controlled or if they're not on optimal therapy. And the greatest risk occurs within 12 months of acute coronary syndrome. So it's important before we modify their risk that we identify these patients who are very high risk for future events. So according to the Multi Society guidelines by we have a definition of very high risk in someone who has a history of multiple major atherosclerotic cardiovascular disease events, one major ASCVD event and multiple high risk conditions. Now a major ASCVD event is defined as recurrent ACS in the last 12 months. History of MI, history of ischemic stroke, symptomatic PAD and that may be defined by history of claudication. ABI less than 0.85, previous revascularization or amputation. High risk conditions are defined as age greater than 75 heterozygous FH, history of revascularization outside of the major ACS event, diabetes, hypertension, chronic kidney disease with the GFR 15 to 59, currently smoking or those patients with persistently elevated LDL greater than or equal to 100 in spite of maximally tolerated statin as well as add on therapy and those patients with the history of CHF. Now the American Association of Clinical Endocrinologists and American College of Endocrinology have also had guidelines with that gives a definition for a very high risk or extreme risk patient, which is a new category unique to the ACE guidelines. Very high risk is defined as established cardiovascular disease or recent hospitalization for ACS, coronary carotid or peripheral vascular disease. A ten year risk over 20%. A patient with diabetes or chronic kidney disease, which we consider a ASCVD equivalent with one or more risk factors or heterozygous FH. Now, extreme risk category are those patients with progressive cardiovascular disease, including unstable angina, after they've achieved an LDL, less than 70? It also includes those patients, which, with clinical evidence of ASCVD who have co-morbidities like diabetes, chronic kidney disease, stage three or four or heterozygous FH. And then those patients with a history of premature cardiovascular disease, that would be a male with an event younger than 55 or a female younger than 65. The ACE guidelines also define some major cardiovascular risk factors. We're familiar with the major ones like advancing age, elevated total cholesterol, non HDL or LDL cholesterol, those with low HDL, diabetes, hypertension, again, chronic kidney disease, smoking, family history. Additional risk factors to consider includes abdominal obesity, family history of hyperlipidemia, increased numbers of small dense LDL, or increased apolipoprotein B, increased particle number, hypertriglyceridemia in the fasting or postprandial state, polycystic polycystic ovarian syndrome. And that dyslipidemic triad, which you'll recognize with the low HDL, high triglycerides and low or normal LDL cholesterol. Then there's nontraditional risk factors which include elevated LP (a), elevated clotting factors, elevated markers of inflammation like hs-CRP or Lp-PLA2, elevated homocysteine and Apo E4 isoform, elevated uric acid or elevated triglyceride remnants. So now let's review some case studies. So the first case I'd like to review with you will be called JW, He's a 37 year old male and he was referred to me for familial hypercholesterolemia. He did have evidence of a non obstructive atherosclerosis noted on a CCLV that was performed at age 26. He had really long standing high triglycerides. His baseline was LDL was 327. When I first saw the first labs that I received, he had some tobacco use. He used snuff, he had hypertension and family history of elevated cholesterol. He was French-Canadian. His grandma died younger than 65 of an MI. So we can see that he's at high risk, according to the Maltese Society guidelines, an extreme risk according to the ACE guidelines. So he had tried and failed. When he first came to me, he had tried and failed rosuvastatin 10. Later he was able to tolerate higher dose. At one point someone had even tried in Atorvastatin 160, which is not a recommended dose. So after our first visit, he was on something for his blood pressure. He was on ARB, he was we were able to get his rosuvastatin up a little bit to 20. We're trying to find that maximally tolerated sweet spot for him and we added on Ezetimibe. Now another risk factor that he had his diet was not controlled. He ate three triple cheeseburgers, three triple cheeseburgers every other day. So that was a problem that needed to be addressed as well. So he did receive some dietary counseling and we talked about that. We'll go into that more later. But it was too little, too late. So the cardiologist called me after JWs first visit and JW had an MI, it required two stents. So when he came back, he by that time was able to he was now on 40 of rosuvastatin and the Ezetimibe. We were able to get Evolocumab a PCSK9 inhibitor approved for him. And I've charted here what his LDLs were over time and the rest of his lipid profile that we had available. So LDL started at 327 after the Ezetimibe and statin, he did achieve greater than a 50% reduction, but LDL was still too high. So then we had the addition of the PCSK9 inhibitor and LDL went down to 35, which is great according to that ACE guideline, which is where we would want him to be with the non HDL level, less than less than 80. So it was at 65, triglycerides would go up and down with him, which again was really related to diet. So these are the guidelines to support the optimal medical management for these very high risk or extreme risk patients. We see that high intensity statin is indicated and then the goal would be achieve a greater than 50% reduction, which we did then add on Ezetimibe which we did, but we were still great, we were still over 70 after Ezetimibe. And so it was reasonable then to add PCSK9 inhibitor and the ACE guidelines echo the same treatment, so provide similar support. So where do we get support for statin therapy in these high risk patients? And you probably recognize a graph like this. This is from landmark clinical trials with statins that show a reduction in LDL. And we see that in both primary and secondary prevention that lower is better. So the LDL achieved versus the event rate and for the amount of LDL is reduced, there is a reduction in cardiovascular events and this provides support for that mantra that we say lower is better. And what about for Ezetimibe? So support for the addition of Ezetimibe comes from the Improve-it trial. That's The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial and this trial looked at high risk patients. It was a secondary prevention study and these were patients who had had an ACS event within ten days whose LDL was still over 50. And it looked they evaluated the efficacy of Ezetimibe with Simvastatin versus simvastatin alone for reducing cardiovascular events. The primary endpoint was cardiovascular mortality, major cardiovascular event or nonfatal stroke, and they achieved, it was a long study over the course of seven years that they were able to achieve approximately 7% reduction that was statistically significant with the number needed to treat a 50, and that's over seven years. For PCSK9 inhibitors, one of the first cardiovascular outcome trials was the FOURIER trial result, which is further cardiovascular outcomes research with PCSK9 inhibitors in subjects with Evolocumab. So time to first event was what this study looked at. The age was 40 to 85. These patients had clinical atherosclerotic cardiac disease. They had an MI or cardiovascular disease within five years or symptomatic PAD with at least one major risk factor or two minor risk factors. The primary outcome of MCE, which was a decrease in nonfatal MI, stroke, coronary revascularization by 20% that was over 2.2 years is a number needed to treat over two years. Is 75. And what we've also learned is that PCSK9s show a good benefit in patients, really benefit patients who are post MI within that are recent post MI let me say, so this is efficacy of Evolocumab on cardiovascular outcomes in patients with recent MI and it was a prespecified subset of FOURIER for secondary analysis. These were patients, like I said, who we looked at, they looked at recent MI less than 12 months versus remote greater than 12 months and the primary endpoint again was composite of cardiovascular death, MI, stroke, hospitalization, or coronary revascularization. Now, the patients who had a recent MRI were at higher risk of recurrent events like we've already identified. But the absolute risk reduction over three years with Evolocumab for the primary endpoint was 3.7% in those with recent MI and 1.1% in those with remote MI. And for the secondary endpoint it was 3.2% in recent MI versus 1.3 in remote MI. So those patients are at higher risk for recurrent events, but they do benefit more from intense therapy with Evolocumab or PCSK9 inhibitor. So as I mentioned, we needed to emphasize a heart healthy lifestyle with our patients, especially with this patient who is eating three triple cheeseburgers every other day. I've listed out here a variety of different diets because there's a lot out there, and all of these would have some level of benefit or have some kind of evidence of benefit. But I personally think they have in common is the diets tend to be rich in fruits, vegetables, plant based, you know, emphasizing plant based foods, rich in fiber and focus on lean proteins, whether that's from plants or whether that's from animal sources. So that's what I see that most of these have in common. I would like to say in the case of JW with his diet, I found out later that those every other day triple cheeseburgers were because his son was getting cancer treatment, and so he was eating those while his son was current, was receiving therapy. So I'm proud to report that one, the son went into remission and that JWs diet also improved. So our next study is RS who is a 75 year old male. He was referred to me with mixed hyperlipidemia, had a history of severe high triglycerides and severe is defined as triglycerides greater than 500 milligrams per deciliter. Now RS had widespread atherosclerotic cardiovascular disease. He had had a TIA, he had had an MI, he had had open heart surgery, he had abdominal aortic aneurysm. He had risks for progression. One, his age being male, chronic kidney disease, hypertension and diabetes. So, again, a patient who we would identify at very high risk or an extreme risk category. So his medications, he came to me on high intensity statin. We added Ezetimibe for the reasons that we talked about and we added Icosapent Ethyl, which we'll talk about support for that. Now, the VA was where he was getting his primary care. They were managing his diabetes and he was on Glipizide and Pioglitazone which doesn't really have a lot of support for this patient, but we'll go over what his these are real life cases. So we'll talk about the benefit, risks and benefits. Now, in terms of his diet, he acknowledged a sweet tooth and of course was counseled on diabetic diet, will go on to more lifestyle counseling as we go on. So as I mentioned, his medical therapy, I have Atorvastatin 80, Ezetimibe 10, Icosapent Ethyl 2 grams bid. And then I mentioned earlier his diabetes was managed by his PCP. We can see over time his LDL was low. That really wasn't the issue. His HDL was low, which is an independent risk factor. But triglycerides started at 496. After the Ezetimibe and Icosapent Ethyl, went to 307 and then with additional lifestyle counseling came down a little bit. What I liked is that as non HDL finally reached below 100 and his sugars improved as well, which really helped the non HDL. So guidelines for optimal therapy again echoes what we did. We achieved. His numbers were already low, his LDL, we had below 70 and that was with the high intensity statin in Ezetimibe. But then I'd like to point out what the ACE lipid management algorithm offered, and they said based on the REDUCE-IT findings that they recommend adding Icosapent Ethyl to prevent ASCVD if triglycerides are between 135 and 499 on maximally tolerated statin therapy. So this is based off the secondary prevention cohort of the REDUCE-IT trial. So let's talk about REDUCE-IT. REDUCE-IT was really the cardiovascular outcome trial that provided support and changed the indication for Icosapent Ethyl to be indicated as an adjunct to diet and maximally tolerated statins to reduce cardiovascular events. Prior to the REDUCE-IT trial, Icosapent Ethyl was indicated to reduce triglycerides. So the REDUCE-IT trial had the primary had a 5-point MACE for the primary endpoint, and that was time to first event for the composite of MI stroke, cardiovascular death, coronary revascularization or unstable angina. And they saw a 25% relative risk reduction that was highly statistically significant, as you can tell from all those zeros, with an absolute risk reduction of 4.8%, a number needed to treat of 21 over five years. Now the secondary endpoint was a 3-point MACE, which is the composite of MI, stroke, cardiovascular deaths, and that reached a 26% relative risk reduction that was highly statistically significant. Again, look at all those zeros with an absolute risk reduction of 3.6%, a number needed to treat of 28 over five years. What I really like about the REDUCE-IT trial is the reduction in total cardiovascular events. And what we saw is there was a 30% relative risk reduction in events over of total cardiovascular events. And you can see how the lines separate early and they just continue to separate over time. So what is the benefit of IPE? So is it because of the triglycerides? Well, like I mentioned, Icosapent Ethyl does lower triglycerides and the treatment group had a 19.7% greater reduction in triglycerides, which was statistically significant. But what I've highlighted here is that the benefit was regardless of triglyceride levels. So even those people who had those patients or participants with less than the 150 milligrams per deciliter on on triglycerides in the study, they also showed benefit. What we seen in additional studies about REDUCE-IT and Icosapent Ethyl is that the treatment group had a 358% greater increases in eicosapentaenoic acid, EPA levels, that was statistically significant. And after one year the IPE increased serum EPA levels by 386% from baseline. And what they saw was that the on treatment levels correlated with decreases in cardiovascular death, MI, stroke, coronary revascularization, unstable angina, sudden cardiac death, cardiac arrest, new heart failure and all cause mortality. So we are seeing that the EPA may be responsible for some of the benefit. We'll need to look into that more. But let's talk about residual risk in triglyceride rich lipoproteins. So why triglycerides are not a target of therapy. We have seen that higher triglyceride levels are linked to adverse cardiovascular outcomes and are recognized as a marker of ASCVD. In fact, for every 50 milligram per deciliter rise in triglycerides levels, this is associated with a 5.8% increase in cardiovascular death. This what we do see is that triglyceride rich lipoproteins are often seen in association with insulin resistant conditions such as diabetes, metabolic syndrome and obesity. It's believed to be causal and prognostic with pathophysiologic evidence, observational and clinical trial data to support an association between elevated triglycerides and cardiovascular event risk. Now, even though we see this association with high triglycerides, what's interesting is that the therapy that reduces triglycerides are not recommended because their clinical trials have failed to show benefit consistent with triglyceride reduction. So that therapy includes fibrates, fish oils and omega three food supplements, as well as niacin. So for lifestyle, I want to focus on the importance of exercise because that was one thing that RS acknowledged is that he wasn’t exercising. And it's not uncommon because those with chronic disease are more likely to report sedentary lifestyle and it should be noted that minorities and lower socioeconomic classes have less physical activity. And unfortunately, less than 30% received counselling. So we really should counsel on the benefit of exercise because compared to less active individuals, more active individuals have lower rates of all cause mortality, heart disease, hypertension, stroke, type 2 diabetes, metabolic syndrome, colon cancer, breast cancer, depression or premature death. Those who exercise have a higher levels of cardiorespiratory and muscular fitness, healthier body mass composition and favorable metabolic profile. And those who exercise have better sleep, health related quality of life, bone health, increased longevity and psychological and cognitive factors. Now there are risks with exercise, and sometimes we need to modify exercise due to limitations. Exercise has been associated with acute cardiac events, including sudden cardiac death and acute myocardial infarction, especially those individuals with structural heart disease and at least in the least physically active individuals. Injuries can be prevented by maintaining regular physical activity, screening patients and excluding high risk patients from certain activities, promptly evaluating symptoms, training fitness personnel to know how to respond to emergencies, and, of course, encouraging patients to avoid high risk activities. So a referral to cardiac rehab is recommended because it would help reduce the risk of injury, and cardiac rehab is recognized as integral to comprehensive secondary prevention care. So it is a Class 1 recommendation from AHA and ACC. And it provides some core components, so it has baseline patient assessment, nutritional counseling, risk factor management, and it also includes psychosocial management, physical activity counseling and exercise training, which is important. So our next case is GW, a 55 year old female. Now she was referred to me for mixed hyperlipidemia and statin intolerance. So when she first came to me, she had no established cardiovascular disease, but she had a left bundle on her EKG, which is always required. So something happened that she had that bundle. I put here that she had chest discomfort, but that's really not accurate. She had these vague symptoms. She when she would start to walk her, she'd feel something in her hands or she'd have these vague symptoms, she really wasn't sure what they were. She had risk factors. And so this is what bothered me. She had hypertension, diabetes, the mixed hyperlipidemia, family history, father died at age 44. So she had a stress test. She underwent a stress test and it came back negative. But I really couldn't let it go because it didn't make sense. That's in my mind with the left bundle and with these risk factors is coronary disease until proven otherwise. And so I center for coronary artery calcium CT scan, and it came back markedly abnormal. She had multivessel disease. And so she ended up getting a cath and angiogram, which confirms Multivessel disease and ultimately required open heart surgery. So although her symptoms were vague, she wasn't asymptomatic. It just wasn't what we would usually call the word typical. So so but even this was too little, too late because her she had very small vessels. And unfortunately, after her open heart surgery, after CABG times four, she had recurrent symptoms. She now she had full blown chest pain. She had a recurrent events and she had an MI. She went to the ER. She underwent angiogram and she had thrombosis in the anastomotic site from Lima to the LAD. So so for GW, we had tried multiple statins. We had tried Ezetimibe and fibrates and everything she was not able to tolerate. After the calcium score, I was able to to get Evolocumab approved for her. We put her on Icosapent Ethyl 2 grams, 2 times a day. After we saw the the thrombosis at that anastomotic site, she was on blood thinners. She at one point she even tried and failed rivaroxaban. For her diabetes we had her on Metformin and Dapaglifozin for diabetes management and heart failure, risk reduction. And she had a good diet. She was very careful to follow a diabetic diet as well as the Dash diet. So this is her therapy. Evolocumab, Icosapent Ethyl, everything else, and then the the anti hypoglycemic agents. Anti-hyperglycemic agents. And then here's her her numbers, baseline LDL was 167 with the PCSK9 inhibitor, and Icosapent Ethyl LDL was at 52, HDL 45, triglycerides remained high. And that I think is linked with the elevated glucose we still have. And her non HDL is less than 100, although we'd like to reduce that less than 80 because again, she's seen as a very high risk patient, an extreme risk patient. So of course the guidelines recommend statin and add on therapy, which we tried. What I would like to highlight here is how the ACE guidelines say that the PCSK9 inhibitors really shouldn't be used in monotherapy except in statin intolerant individuals, which was the case we have here. So what contributes to residual risk? I like the slide from Dr. Ridker and he outlines two studies, PROVE-IT and IMPROVE-IT that talk about residual risk in these patients. So PROVE-IT were those patients who were randomized. They had Pravastatin versus high intensity Atorvastatin and IMPROVE-IT we already talked about which was simvastatin plus or minus Ezetimibe. And looked at what was the drivers, what are the drivers of residual risk? So we see in blue the residual inflammatory risk is about a third of the case by itself, inflammatory risk. Residual cholesterol risk only accounts for 13 to 14%. If you count both residual inflammatory and cholesterol risk, then that's an additional 14%. What I'd like to point out is a third of the time it’s neither. It's neither inflammatory or residual cholesterol risk. And so what is that? What what could that be? Well, let's look at residual thrombotic risk, because I think that played a role in GWs case, because platelet activation and aggregation is a driver for symptoms of coronary thrombosis. So what are atherothrombotic risk factors? That includes age greater than or equal to 65, diabetes, a second prior MI, multivessel CAD which she had, chronic non end stage renal dysfunction. Now therapy is of course with platelet inhibitors, there's aspirin and there's the oral p2y12 inhibitors which are listed here. Clopidogrel and Prasugrel, as well as reversible binding that do not require metabolic activation like Ticagrelor, which also has an indication in ASCVD prevention. But what about anticoagulants in drugs in sinus rhythm? So oftentimes when we think about thrombotic risk, I think about arrhythmias, AFib and thrombotic risk of thrombotic stroke. But there is a role for anticoagulant drugs in sinus rhythm to prevent recurrent events, and that's with a factor 10A inhibitor that has evidence rivaroxaban. And the reason why is because they inhibit action and or formation of thrombin. Thrombin plays a pivotal role in both coagulation and activation of platelets and can reduce the risk of arterial thrombotic events. So the dose that was used in the COMPASS trial was 2.5 milligrams, and this is a quarter of the dose of the standard dose used for atrial fibrillation. And what I like this quote that this was really kind of a sweet spot balancing efficacy and safety by favorably affecting the residual risk in patients with established stable ASCVD on appropriate background medical regimen. So let's talk briefly about the COMPASS trial. And this is the Cardiovascular Outcomes for People using Anticoagulant Strategies. So this had the primary endpoint was composite of cardiovascular death, stroke, or MI. And there were three groups, so they were randomized either to rivaroxaban with aspirin, rivaroxaban alone, or aspirin alone. And it should be pointed out that the study was stopped after 23 months for superiority in the combination of rivaroxaban with aspirin. And what they found was a 24% relative risk reduction that was statistically significant. And they also found an 18% reduction in all cause mortality in that Rivaroxaban aspirin group. Now, major bleeding events occurred in more in the riva aspirin group, but it should be noted that 97% of those patients did in that group did not have a major bleed. I thought we'd also talk about an old therapy that has been used to interrupt the inflammation pathway, and that's colchicine. And it's often used for its anti-inflammatory actions, like to reduce pericarditis, but they've used it now in two studies, both in the acute phase as well as in chronic. So the first study is the, we’ll briefly review, is COLCOT, which was looked at the efficacy and safety of low dose colchicine after myocardial infarction and they enrolled patients within 30 days of the immediate acute coronary syndrome phase. The primary endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, ischemic stroke or urgent revascularization for angina. And that had a 23% relative risk reduction that was statistically significant. And they pointed out that those enrolled within three days of the qualifying ACS event did better than those that were enrolled later. Now there was pneumonia reported as a serious adverse event in the treatment group. The other study, LODOCO2, looked at colchicine in patients with chronic coronary disease and they enrolled patients with coronary artery disease stable for at least six months. The primary endpoint was composite of cardiovascular disease, death, spontaneous MI ischemic stroke or ischemia driven coronary revascularization that reached a statistical significant with a relative risk reduction of 28%. Now, in this study, this was well tolerated and there were no increase in infections noted. I'd like to point out in this case talk about women and heart disease, because I think it played a role in this case, because we talk a lot about women's presentations are different. And I think it's important to remember that cardiovascular disease is a leading cause of death for women in the US and accounts for one in three female deaths. And although women will have similar risk factors as men, the way those risk factors impact the heart disease may be different. In addition, women have some nontraditional risk factors. So for example, women tend to have a higher prevalence of hypertension and it tends to be less controlled than men. With dyslipidemia, this is the highest population attributed risk compared with all other risk factors. On a positive note, however, Atheroma Atheroma regression and LDL lowering may be greater for women on statins compared to men. So that's a positive. In terms of obesity, the impact of obesity on development of CAD is greater in women than in men. For diabetes, there's three times the risk for fatal CAD compared to non-diabetic women. There's higher mortality in than diabetic males, lower revascularization rates, higher risk for developing heart failure than diabetic men, and stronger risk for stroke in women than in men. And for smoking, women who smoke have a 25% increased risk for CAD than men. Now, we mentioned that women have nontraditional risk factors, so those include preterm delivery, hypertension pregnancy disorders, gestational diabetes, breast cancer treatments, autoimmune disease, and as well as depression. We often talk about differences in symptom presentation because it's important to recognize that women may present differently. And it's important to recognize symptoms for accurate diagnosis. And that was really the situation with the case I discussed is her her presentation was really different. I want to point out that both men and women most often experience chest pain, but they may experience other symptoms. Men as well as women. And so we need to refrain, it's hard to do is refrain from using terms like typical or atypical. So, for example, men may have diaphoresis more than women. There may be no difference in the experience of symptoms like stomach or epigastric pain, indigestion, left arm, left shoulder or right arm or right shoulder pain. Now, women will experience pain between their shoulder blades, neck pain, palpitations, jaw pain, nausea, vomiting, fatigue and shortness of breath more than men. Also, it should be noted that women are more likely to minimize the importance of symptoms. And I felt like that happened with GW as she would bring it up and she couldn't quite put her finger on it. And she it would been easy to dismiss it. And I think that may be because of the way women communicate. They may use emotions to talk about emotions, how they feel about it more than talking about facts. And so there's that. They also have that fear that they're going to be dismissed. And so they may dismiss it themselves before giving you a chance to dismiss it. So something to think about. So in summary, ASCVD is a complex progressive disorder. It exists on a continuum from subclinical disease that can be chronic, stable or lead to acute coronary syndrome. Those with acute coronary syndrome and those within the first two years of an event are at the highest risk for recurrent events. Guidelines informed by the cardiovascular outcome trials provide us with tools to identify very high risk and extreme risk patients and those therapies with demonstrated benefit to reduce risk. And optimal medical therapy and lifestyle modifications are vital to prevent recurrent events and to control risk factors that contribute to residual risk. And so our final take home message is there is no cure for ASCVD. Once it's there, there's really no cure. So we're truly going to prevent it, we need to start it before it develops. Thank you.