Manesh R. Patel, MD, Duke University 

 I think the future is bright. I think there are new therapies that are coming to light, which hold the promise of improving risk or reducing risk in our patient populations. There are novel agents for lipid modification that are allowing us to achieve lower and lower LDL cholesterols even with more simplified dosing regimens and perhaps less resource intensive. There are also novel targets like LPa, which may be particularly important in disease states like peripheral artery disease. And then I think we’re learning more about the use of antithrombotic therapy and low-dose anticoagulants like rivaroxaban. There will be more data out coming from the VOYAGER trial and others truly showing the broad benefits of such strategies. There are a lot of promise out here. There’s new diabetes agents and combination agents that people are talking about. That being said, the more therapies that we learn are efficacious, the more we need to be able to tailor and personalize those therapies. And I do think that the broad atherosclerosis approach of treat every patient the same way probably will shift even more to an individualized approach. I will take for example, the patient with peripheral artery disease. You may choose to treat them differently than a patient with coronary disease or a patient who has PAD and diabetes and how do you – or how one sort of stages the different therapies. And that’s only going to get more complicated as we have new approaches on the horizon. I hope in concert with all of these new and exciting agents that can reduce risk that there is an equal effort to study implementation science, real-world data to enable clinicians to really understand how to best personalize and how to deliver care to patient populations.

I really want to thank you for your attention here. I think if you are feeling a bit overwhelmed by all of the data and new agents and new outcomes, you're not alone. As a clinical community the pace of discovery has absolutely accelerated. But I think the more that we can work together as a clinical community and we can work as multidisciplinary care teams, the better we can do to really systemize therapy across these populations. And I do take particular heart in dedicated trials in these high-risk populations. For example, VOYAGER PAD where we are really looking at specific population at a specific time and the right outcomes that are relevant to that population rather than trying to do one size fits all. And I hope that our research continues to move in that way to enable us as clinicians to understand how to personalize the preventive therapy and speak to our patients about risk and how to avoid the worst complications of atherosclerotic vascular disease.

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Marc P. Bonaca, MD, MPH, of the University of Colorado School of Medicine, comments on the potential to personalize treatment with emerging therapies in the pipeline to better manage patients at high risk for cardiovascular disease in the future. 

Cardiovascular Disease: Future Perspectives 

 In the management of CAD/PAD, there are so many unmet needs still unfortunately. Think about this for peripheral artery disease, we all know that if the left main artery, the main artery to your heart or the lAD and the circumflex disease or the right coronary three vessel disease is present, you do worse. In the peripheral artery system, we do not even have a scoring system we've agreed upon for future limb loss. So just even anatomic criteria that we agree upon and the management of that, is just a first step. But the biggest areas of unmet need, I think for both drug development and patient care is verifiable patient reported outcomes that we can measure in our patients with PAD. And for our CAD/PAD patients, finding ways where we can get proven therapies to them in consistent fashion. So even though it sounds simple, adherence is one of the hardest things we must solve and getting our patients' cholesterol numbers down, getting them chronically on antithrombotic therapy that they can tolerate without bleeding and getting them to get their blood pressure down. Whether it is with drugs or device therapy, are all going to be critical for the future of what we do for our patients of cardiovascular disease. And if we have learned anything from the pandemic, we have learned that we have to all work to bend the curve for cardiovascular disease just as we did with the pandemic, because last year and the year before more people died from cardiovascular disease than almost anything else. And for last year in the pandemic, more people died from cardiovascular disease than even with COVID. It's significant opportunity to improve our patient's health, probably by getting innovative therapies at high adherence to our patients.

You know, I find that as we go through medicine, we continue to potentially relearn things or learn new things that have been done. But one of the reasons I think all of us are in the healthcare field, is to get the joy of having people feel better and live longer, healthier lives. In fact, our biggest challenge now is to find ways to improve the health of our population in an equitable fashion around the world. And the only way to really do that is to get people more engaged in their own health and that does require, in our little episodic ways, in which we care for our patients, thinking about ways to take care of their entire health and finding out what matters to them. And that is some of the fun- most fun things we do. I start a lot of my clinic visits by asking my patients, what do they do on most of their days, what is the average day that- what gives them fun, what is limiting them, how do we make them feel better. In fact, Dr. Caleb was a mentor of mine once in the CIC at Duke taught me that we should only do things for patients that make them live longer, feel better or avoid unpleasant events, and things like being in the hospital or feeling like you can walk or do more of your activities. And really treating the whole patient's health through that lens has helped me throughout my career because I find that when people get to do things that improve their quality of life, they enjoy it and come back to see us and say, hey, thanks, I was able to do this, or I was able to stay on this therapy and be healthier longer. Now, part of prevention or even treating people after we've intervened on them, the hardest part is getting them to recognize that the risk is still high and that taking these therapies reduces their future risk. I would suggest that treating the whole patient is really the only way to have a meaningful and fun long-term career in medicine.

I think many clinicians that see patients with diabetes, patients with atherosclerotic vascular disease or patients with a combination of both, there is a struggle now because there’s so many different therapeutic options and we have a short period of time with our patients. Prevention is challenging because patients do not feel that and what you're trying to prevent like heart attack and stroke, they don’t know that they're not having those events. They’re taking therapy for prevention. I think it is difficult. And there are also a lot of crossovers now between specialties. For example, we have targeted diabetes therapies like the SGLT2 inhibitors, which have benefits in multiple populations that aren’t related to their glucose-lowering ability but are targeted therapies, things like GLP-1s, lipid-lowering, and so on. I think the biggest problem we face is clinical inertia and in some ways paralysis because there’s so many different clinicians in the mix and we’re all thinking about different things. And the patient is already taking a lot of drugs. So how do we improve the provision of care. I think this is the core area where multidisciplinary care teams are really necessary to align on identification of patients at high risk, and systematic adoption of proven therapies to reduce risk. It can’t be sort of willy-nilly in the clinic, today I had enough time to think about it because then we end up with big gaps in care. We know from population data sets that there are a lot of patients, particularly PAD patients that are under-treated that aren’t even getting statins. So multidisciplinary care teams allow us to think about a patient in a holistic fashion. A patient is not a PAD patient or a CAD patient or a diabetes patient. They’re your patient and they have all of those risk factors that you need to manage and then you need to manage that not only hierarchy of risks but then hierarchy of therapies and what provides the broadest, most important net benefit for that patient that you're seeing. And I think a multidisciplinary care approach enables you to think about those patients in a very holistic way. Now that alone may not be enough to really improve the provision of care and I think that implementation science and systems of care guided by multidisciplinary care teams that enable the systems to look at patients broadly across a population, identify high risk, and then you use algorithms to introduce therapies that have broad benefits with the support of pharmacists, nurses, a care team approach can do a much better job at improving the provision of care than a single clinician. And I say that personally because I know many times a patient walks out of my office and they’re probably not on optimal therapy because we didn’t have time, because there are payor issues, because of other things. And it’s very difficult as an individual patient/clinician combination to always get it right. And I think multidisciplinary care models and enhanced systems of care are necessary to really care for these complex patients.

 When I'm taking care of patients with my colleagues in a team-based format, one of the biggest things I enjoy is being able to have the back and forth sort of relationship with the patients and my colleagues as we take care of that patient. For my vascular surgical colleagues, one of the things I enjoy the most about is their innovative ways of getting blood flow to the limb. And often our interaction of learning how to better treat all their arteries. I say this all the time to my patients that I can fix a pothole with a stent, my surgical colleagues can put a bypass around the problem, but we really need therapies that treat all the highway. And so, working with my vascular surgery colleagues or my cardiology colleagues, we often think about systemic therapies for diseases that are chronic and systemic like cardiovascular disease. With my podiatry colleagues, I really appreciate their attention to detail and wound healing, and in identifying patients that have reduced blood flow in their limbs. And understanding that even if we work to get more blood flow to them, then it's not just more blood flow, but chronic antithrombotic therapy, chronic lipid lowering therapy and chronic control of diabetes that will lead to better outcomes for your patients' limbs, toes and obviously all the things that many of us want our patients to stay mobile without morbidity or mortality.

Unmet needs in the management of coronary artery disease and peripheral artery disease, and advice for working with patients and other healthcare professionals to optimize care for patients at high risk for cardiovascular disease.  

Optimizing Cardiovascular Risk Reduction 

Putting it all together, how do you decide what you’re going to tackle for any given person or anybody you see in clinic around cardiovascular risk reduction. I think about the things I can have the biggest effect on, and some of them are the hardest. If the patient is smoking, we know that quitting is the single biggest thing they can do to reduce their cardiovascular risk. If the patient has high blood pressure—30% of the people with cardiovascular disease do—that’s the next most modifiable risk factor that will lead to global population improvement and improvement for our patients at cardiovascular risk. 

Let’s go to the next potentially treatable version, which is usually our cholesterol lipid. For those patients who aren’t at goal, who are at high risk, a moderate-intensity to high-intensity statin should be given, specifically in those patients with diabetes or those with high risk for future cardiovascular events. If my patients have had cardiovascular disease, we know the disease is present. If they’ve had a heart attack or a stroke, then they’ve got coronary artery disease [CAD], they’ve got peripheral artery disease [PAD], they might have had a limb event. In patients for whom we should have been doing those other things, but now they’ve still had the event, I’ve started to think about using what I’ll call the dual-pathway therapy: either a low-dose rivaroxaban plus aspirin, or I’ll come up with other ways to use specific agents. Often it’s the dual pathway, but if the patient just had an angioplasty or an MI [myocardial infarction], it may occasionally be dual-antiplatelet therapy [DAPT] to reduce their risk. Finally, for those patients with diabetes, we have an armamentarium of new agents, like SGLT2 inhibitors. That’s a lot of stuff to give a patient at once. I figure out what the patient’s highest-risk issues are and try to tackle those. Some patients have all those risk factors but may have some very specific ones you can home in on.

 We’ve learned a lot about the risk profile of patients with peripheral artery disease and coronary artery disease, particularly in polyvascular disease. These are high-risk patients, and their risk profiles and their response to therapy differ depending on who they are. What I’ve learned about antithrombotic therapy and either long-term DAPT or long-term dual pathway with aspirin and rivaroxaban is that both have utility. I think of dual-antiplatelet therapy in high-risk patients with ACS [acute coronary syndrome] that we may continue long term. However, I see a lot of patients with chronic vascular disease who haven’t had a recent MI or who are on aspirin alone. In that setting, adding rivaroxaban has shown the greatest net benefit. 

For example, for the polyvascular patient with PAD and CAD or the patient with high-risk chronic coronary disease who hasn’t had a recent MI or vascular intervention, the dual-pathway therapy has very good efficacy, the bleeding appears to be tolerable, and there’s a net benefit overall if you exclude patients who are very high bleeding risk. Patients with PAD, particularly those who don’t have coronary disease—about two-thirds of them—are very different. They’re very high risk. The risk is driven by limb outcomes, and in that setting it’s different from coronary disease. 

We really have no data to support dual-antiplatelet therapy as a strategy. There was a trial called CASPER that looked at aspirin and clopidogrel vs aspirin alone in patients with PAD after intervention. There was no benefit but more bleeding. We also know that warfarin doesn’t work here. This becomes quite clear. The patient with PAD, particularly without CAD, who has undergone an intervention, really the only choice is aspirin and rivaroxaban vs aspirin alone. As an alternative, there are other agents that have been studied in the past like vorapaxar, but the most commonly available agent that is labeled for this chronic PAD patient population is aspirin and rivaroxaban. 

In my practice, we need to do more for antithrombotic prevention with CAD and PAD and the combination of both. We need to be more thoughtful about risk even in patients who appear to be stable because we know that they’re not. They’re stably unstable, if you will. We have different strategies we can turn to that have shown efficacy: DAPT, aspirin and rivaroxaban, and for chronic PAD or CAD, I tend to reach for aspirin or rivaroxaban.

I like to individualize my approach to patient care and engage in and share decisions with my patients. So I tend to risk stratify. There are some very complicated risk-stratification algorithms. I tend not to do that. I use a more simplified approach. The first thing I think about when I see a patient in the clinic is their vascular risk. If they have symptomatic coronary disease, they’re at high risk. If you add something to that—like diabetes, heart failure, multivascular disease, CKD [chronic kidney disease]—then they’re very high risk. I know that patients with peripheral artery disease are high risk, particularly for adverse limb events, particularly if they have concomitant coronary disease. If they’ve ever had an intervention to their limbs or an amputation, then they’re at very high risk of limb outcomes. Those are the patients I really worry about.

I obviously want to think about bleeding risk. If they’re a high bleeding risk, I’m probably not going to add more intensive antithrombotic therapy. But if they’re not at high bleeding risk, I’ll usually add something. In the case of acute coronary syndrome, a patient who is tolerating DAPT may continue that long term. That’s reasonable. But most of these patients are on aspirin alone, so I’ll try to add a second agent. That tends to be low-dose rivaroxaban for polyvascular patients with PAD.

Drs Marc P. Bonaca and Manesh R. Patel discuss the rationale for individualized treatment plans for patients with type 2 diabetes at high risk for cardiovascular disease.

Individualizing Treatment to Reduce Risks of CVD 

One of the most telling trials recently is the COMPASS trial, which studied patients with stable CAD [coronary artery disease] and PAD [peripheral artery disease]. It took 24,000 patients who had coronary artery disease from roughly 558 centers, and it randomized them into 1 of 3 regimens. One was just aspirin therapy, another was 5 mg of rivaroxaban twice daily, and the third was 2.5 mg of rivaroxaban plus low-dose aspirin. That trial stopped early, showing that there was a significant reduction in MACE [major adverse cardiovascular events] for those patients—a relative risk reduction of about 25% to 26% for a hazard ratio of 0.76 in patients who got the 2.5 mg twice daily of rivaroxaban plus aspirin. Significantly, that showed not only a reduction in some myocardial infarction [MI] and significant reduction in CV [cardiovascular] death but also a reduction in stroke, which was fairly telling. What that did was open our eyes. I started talking about platelets leading to clots in that vessel, but there’s also that other pathway of antithrombotic therapy, the clotting that happens through the thrombin pathway.” This dose is potentially the most studied dose of rivaroxaban because it was studied in ATLAS and now COMPASS. The 2.5 mg twice-daily dose of rivaroxaban, when coupled with low-dose aspirin, seems to reduce the cardiovascular events the most; there’s no free lunch.

People often ask, how did that do compared with bleeding. Just to highlight again, it was roughly a 4% rate in the population for those who got 2.5 mg of rivaroxaban twice daily plus aspirin, and the 2.5 mg twice daily plus aspirin once daily. Comparing that with aspirin alone once daily, the event rate was 4% vs 6% in the CAD population. If I look at the CAD population from Stuart Connolly’s publication in The Lancet, there’s a 2% absolute-risk reduction, or a hazard ratio of 0.74. I have to treat about 50 patients broadly who have coronary disease, in some of these elevated-risk factors, chronically with this therapy to prevent 1 of these MACE events. That’s a pretty powerful therapy in those patients.

How do we reduce the risk of our patients with a high risk for cardiovascular events who have diabetes. The COMPASS trial, as I highlighted, showed some really interesting findings. I took home the COMPASS trial by saying, “The more your burden of vascular disease, the more benefit you got.” If you have coronary artery disease—CAD and PAD, 2 vascular beds—you got a bigger benefit. If you had coronary disease, lower-extremity disease, and carotid disease counted in the PAD group, it seemed like you got more of a benefit. 

Who else benefits? They said CAD plus kidney disease. Kidney disease is another vascular bed to me. We just happen to figure it out with the creatinine. The other high-risk group were people who had diabetes and coronary disease. I think about diabetes as multivessel disease because it affects everything, so diabetes can also be considered as a polyvascular component. For people with diabetes, which affects all vessels and coronary disease, it’s just another vascular bed. When I put those populations together, those findings have shown us that the patients with diabetes, just like the polyvascular patients, had a significant reduction with aspirin and 2.5 mg twice daily of rivaroxaban compared with aspirin. It had a hazard ratio of 0.74, almost a 2% absolute-risk reduction and a significant reduction in MACEs, although small numbers, and also in limb events. There were some small numbers, but they were at least 50% less than the rivaroxaban-treated group.

The VOYAGER PAD trial looked at the combination of low-dose aspirin and a low-dose anticoagulant, rivaroxaban 2.5 mg twice daily, in a very specific population. This was a PAD population undergoing revascularization for either clot occasion or critical limb ischemia, and it looked at the reduction or the benefit in terms of both major adverse limb events and cardiovascular events, what I like to call irreversible harm events of the heart, limb, or brain. What we learned from VOYAGER PAD was that that combination, which had been shown to be efficacious in chronic coronary and peripheral artery disease in the COMPASS trial and even in patients with acute coronary syndrome in the ATLAS trial, was that it was again efficacious for this broader outcome in patients with peripheral artery disease with efficacy apparent both early and long term—even 3 years after the intervention.

An additional thing we learned from VOYAGER PAD has to do with the safety of combining the strategy with antiplatelet therapy. Patients who get stenting in the coronary or periphery—here we’re talking about PAD—often will get a short course of dual-antiplatelet therapy [DAPT] for stent protection. That’s not really data driven in PAD, but it’s often done. What we learned was that adding rivaroxaban—starting at the time of revascularization shortly after with DAPT and then just stopping DAPT when you no longer needed it but continuing rivaroxaban long term—was safe. Overall, there was no interaction for bleeding on the basis of clopidogrel, and the benefit of the low-dose anticoagulant was very clear on top of clopidogrel. The way I take that is that DAPT is not enough to prevent acute limb ischemia. It’s not enough to prevent MIs and strokes in this population. The benefit of rivaroxaban in relative and absolute terms was consistent whether you choose to use it, and it was safe to follow that strategy and initiate the rivaroxaban right away. We did see a trend for less bleeding in those who had shorter durations of DAPT, a month or less rather than longer durations, but obviously that’s something you need to individualize for each patient.

Implications for treating patients at risk of cardiovascular disease with rivaroxaban plus aspirin based on the COMPASS and VOYAGER PAD clinical trials. 

Manesh R. Patel, MD, Duke University

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