Activity Transcript

Herbert D. Aronow, MD, MPH, FSVM, FACC, FSCAI: Hello, I'm Herb Aronow, current president of the Society for Vascular Medicine and medical director of Heart and Vascular for Henry Ford Health in Detroit, Michigan. Welcome to this program entitled, "What Vascular Specialists Need to Know About Antithrombotic Strategies in Peripheral Artery Disease Post-Revascularization."

The management of patients with peripheral artery disease (PAD) undergoing lower extremity revascularization can be complex. These patients face multiple challenges, including a long-term risk of ischemic events, such as major adverse cardiovascular events (MACE) and major adverse limb events (MALE). In this program, the faculty and I will discuss the data for and role of antithrombotic therapy, including dual pathway inhibition for patients with PAD undergoing lower extremity revascularization.

In the first segment, Jeffrey Washam will review the importance of effective antithrombotic therapy to reduce the risk for MACE and MALE in patients with PAD undergoing lower extremity revascularization. In the second segment, Eric Secemsky will outline the latest clinical trial data on dual pathway inhibition in patients with PAD post-revascularization. In the last segment, I'll discuss how to best incorporate antithrombotic therapy into the management of patients following lower extremity revascularization.

Jeffrey B. Washam, PharmD, FAHA: Hello, my name is Jeff Washam and I'm a clinical pharmacist in Duke Heart Center and consulting associate in the department of medicine at Duke University. Today I will be speaking with you in this segment about, "Antithrombotic Therapy for PAD Treatment Post-Revascularization: A Primer."

The current estimate of the prevalence of PAD in the United States is approximately 7% in adults aged 40 and over. This would correspond to 8 to 12 million persons living with PAD and the estimate varies depending on the methodology used to calculate the prevalence. However, PAD is not just a problem in the United States, but it's a global healthcare problem, as well, with an estimated over 230 million persons worldwide living with PAD.

This slide depicts the natural history of PAD. Intermittent claudication and chronic leg ischemia are the 2 most common indications for revascularization procedures in patients with PAD. These would also include patients with symptomatic PAD.

This slide highlights the risk in both MALE and MACE in the 5-year window once patients develop symptoms. As you can see, the rates of MALE are ~25% over that time period and the risk of MACE are 20% to 40%. There are significant elevations in risk once patients begin to have symptoms of PAD.

Lower-extremity revascularization procedures occur commonly in this country. Once patients have a revascularization procedure, they're at heightened risk for both MACE and MALE. This has been observed in both clinical trials, as well as in registry data. In the EUCLID trial that studied ticagrelor in PAD a 4-fold increase in acute limb ischemia was observed in patients with a history of revascularization as compared to patients who enrolled into the trial based on ankle-brachial index (ABI).

Data from the REACH registry shown on this slide, demonstrated that 2-year hospitalization rates were highest in patients with a history of revascularization or amputation as compared to patients that were asymptomatic or had symptoms of claudication at baseline. The outcomes they were looking at with respect to reasons for hospitalization were all major adverse limb event reasons for hospitalization.

Antithrombotic therapy has been a cornerstone therapy in the management of patients with PAD, and in those patients with PAD that have undergone revascularization procedures. However, focused, clinical trial data, specifically on the comparative efficacy of regimens is overall lacking, especially until recently.

The 2016 American College Cardiology (ACC)/American Heart Association (AHA) guidelines on the management of patients with lower extremity PAD provide some information. Several of the recommendations are provided on the screen as you're looking at it now. The single class I recommendation was for monotherapy or single antiplatelet therapy with aspirin alone, or clopidogrel alone, to reduce the rates of myocardial infarction (MI), stroke, and vascular death in patients with symptomatic PAD. Just to highlight, these were recommendations to reduce the risk of MACE events and not MALE events, largely due to the fact that the evidence base that was used to derive these recommendations was from patients with polyvascular disease, which looked at subgroups of patients with PAD within that.

For patients that have undergone a revascularization procedure, a single recommendation was in these guidelines as well. This was for the use of dual antiplatelet therapy (DAPT), aspirin and clopidogrel, which may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD following a lower extremity revascularization. I think it's important to note that this received a 2B class recommendation, essentially meaning that this is not a favorable strategy to use in a wide group of patients. It's more of a singular case-by-case risk benefit selection.

Given the lack of comparative clinical trial data for comparing antithrombotic regimens following a revascularization procedure, significant variation in use of antithrombotic regimens following a revascularization procedure has been observed. The data shown on this screen is from the Society of Vascular Surgeons Quality Initiative looking at antithrombotic and antiplatelet therapies at the time of discharge. One thing that was evident from this was the regimen that was used at the time of discharge was significantly affected by the antithrombotic therapy that patients were on at the time they presented. However, I would like to call your attention to the third column on the table, which was patients that were not on anticoagulation and not on DAPT at the time of the procedure. In those patients, there was a lot of variation across the different regimens that were used, including approximately half of the patients were discharged on DAPT; approximately 30% were discharged on aspirin monotherapy; approximately 20% were discharged on P2Y12 inhibitor monotherapy; and almost 7% were discharged on no antithrombotic therapy. There is a lot of variation in multiple registries and observations, which have demonstrated this.

The present slide shows some select regimens that have been used historically, in registries, from subgroups, and in recent clinical trials across a wide range of different populations that have undergone revascularization procedures. One thing that I would like to highlight is that the first 3 regimens, which include the aspirin only regimen; clopidogrel with or without aspirin; and then vorapaxar with aspirin, with or without clopidogrel regimen, are all fully focused on platelet inhibition. The last regimen, which of these regimens is the only one that's been assessed in the immediate post revascularization period, is the only regimen that combines an antiplatelet in the form of aspirin with an anticoagulant agent in the form of rivaroxaban. This type of strategy, one that combines an antiplatelet with an anticoagulant, has been termed a dual pathway inhibition antithrombotic strategy. Aspirin plus rivaroxaban together is an example of a dual pathway antithrombotic inhibition strategy.

The rationale for using a dual pathway inhibition strategy in patients with peripheral disease is based on pathophysiologic and observational data that states and supports that in vascular disease thrombotic events generally occur with the disruption of an atherosclerotic plaque, as well as with superimposed thrombosis. There's obviously a cross link between these 2 systems. The disruption stimulates platelet activation, which subsequently activates thrombin and the coagulation cascade, hence supporting the rationale for potentially using inhibitors of each of the 2 pathways concomitantly.

More discussion on the dual pathway inhibition will occur in the upcoming sessions in this program. However, before moving on, it is important to note that in patients with PAD, a number of previously established interventions are important and should always be included both in the management of patients with symptomatic PAD, asymptomatic PAD potentially, and also in those who have undergone revascularization procedures.

The first is smoking cessation in symptomatic patients. This would include all patients going for a revascularization procedure. Smoking cessation has been associated with a lower risk of critical limb ischemia (CLI) amputation. Secondly, lipid management. Statin therapy receives a class I recommendation in the 2016 ACC/AHA guidelines for management of patients with lower extremity PAD. The use of statins has been associated with reduced rates of major adverse cardiac and major adverse limb events in patients with PAD. Also, recent data from patients enrolled in polyvascular disease trials show emerging potential treatment benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in patients with PAD. Controlling blood pressure has been established to reduce MACE, and is a recommended class I strategy in hypertensive patients with PAD. Glycemic control is also a recommended strategy as potentially beneficial in patients with chronic limb ischemia to reduce limb related outcomes. Continuing on that note, more recent data from polyvascular disease and high-risk diabetic population trials have shown that sodium-glucose cotransport-2 (SGLT2) inhibitors, select agents, as well as agents from the glucagon-like peptide-1 (GLP-1) agonist class have shown significant reductions in MACE and amputations in patients with vascular disease. Lastly, structured exercise programs, both in the form of a supervised program which takes place in a healthcare facility with direct supervision from a qualified healthcare provider, as well as a structured home-based program. This type of program is essential for patients who do not have access, transportation, a number of other factors that may limit their ability to attend a supervised program, but in this structured home-based or community-based program, the exercise regimen is prescribed by a healthcare provider. It is self-conducted by the patient, and then there's ongoing guidance from the healthcare provider on adjusting the exercise prescription. And each of these regimens has shown the ability to improve functionality, quality of life. Thank you for joining.

Eric A. Secemsky, MD, MSc, RPVI, FACC, FAHA, FSCAI, FSVM: Hello. My name is Eric Secemsky, I'm the director of vascular intervention at Beth Israel Deaconess Medical Center. It's my pleasure to discuss today, "Dual Pathway Inhibition Following Lower Extremity Revascularization: The Clinical Evidence."

Trials of medical therapy for PAD have overall been underwhelming. We've seen over the last 3 decades attempts to identify agents to improve both MACE among patients with PAD as well as MALE with very little success.

Over the next few minutes, I'm going to go through some of the major trials looking at both antiplatelet therapy and anticoagulants that have attempted to improve limb outcomes for patients undergoing endovascular or surgical revascularization without much success. Following that, I'm going to spend some time covering the VOYAGER-PAD study and speak a little bit more about the evidence that supports the dual inhibition pathway.

The first study I want to highlight here is the CASPAR trial. This is a really important surgical study looking at patients who have below the knee PAD, who are undergoing unilateral bypass grafting. They were randomly assigned to a program of aspirin and clopidogrel vs aspirin alone. On the left here, you can see the Kaplan-Meier curves for their primary outcome. You can see that there is no significant difference in the rate of repeat interventions, occlusions, and amputation among patients who were randomly assigned to aspirin and clopidogrel vs aspirin alone. Conversely, there was a risk for being on DAPT over the long term. You can see highlighted in the table both an increased risk of all-cause mortality as well as an increased risk of moderate and severe bleeding with a regimen of aspirin and clopidogrel vs aspirin alone.

This really moved away from the idea that DAPT, in particular for grafting below the knee, was an improvement or can lead to improved outcomes over aspirin alone.

If antiplatelet therapy isn't enough, maybe an anticoagulant therapy would be better. There was a separate trial that looked at infrainguinal bypass grafting with the use of warfarin vs aspirin. In this trial, the idea was a higher international normalization ratio (INR) of warfarin dosing might be more effective than aspirin therapy alone. What they found was, instead, not only was there a failure to improve overall outcomes for bypass grafting with similar rates of graft occlusion, there was, again, a much greater risk of hemorrhagic stroke and overall hemorrhage in patients who were randomly assigned to warfarin.

Again, this moved us quickly away from the idea that an anticoagulant such as warfarin is the right therapy, especially at higher international normalization ratio (INR) dosing.

What about on the endovascular side? On the endovascular side, we have very limited data to evaluate the importance of DAPT after endovascular intervention. Most of the data is really taken from the coronary literature. There was this one study called the MIRROR trial, which looked at 80 patients who were undergoing an endovascular procedure. They compared DAPT with clopidogrel and aspirin vs aspirin alone. At 6 months, you can see there was a suggestion of an improvement in freedom from target lesions in revascularization if aspirin and clopidogrel was used over aspirin alone, but by the time it got out to 12 months, this signal was no longer apparent. Overall survival also did not differ between the 2 groups.

Again, on limited data, this really did not suggest any benefit of DAPT for reducing target lesion revascularization after an endovascular approach.

We also have some real-world data that looked at DAPT to kind of supplement what we are lacking on the randomized trial data. This is a more recent study looking at 754 limbs treated, the majority of which had been undergoing treatment for CLI and treated with an endovascular approach. You can see on the Kaplan-Meier curve that after propensity score waiting that patients were no longer different in terms of the benefit of survival from amputations over the long term, after 36 months, between the DAPT group and the monotherapy aspirin alone group.

If we summarize where we stand with both DAPT as well as anticoagulation, we know that, in particular for DAPT, that there is no change in patency for revascularization procedures. We saw both for surgical procedures as well as for endovascular procedures. There's really no clear improvement in long-term limb outcomes, unlike what we see sometimes for cardiovascular events, where there is some suggestion that maybe patients with coronary disease and PAD may have a benefit for longer term DAPT. The risk is an increased breeding, potentially associated with other adverse outcomes. We saw an increased risk of potential death in a study called the DAPT study, but also, this was a redundant mechanism of antithrombotic action.

We know that both aspirin and clopidogrel working on the same pathway -- inhibiting platelets and completely ignoring the coagulation cascade. Is a redundant approach to treating platelets the right way to improve therapy for patients undergoing peripheral intervention? That really leads us to what we're looking for and what we're going to be discussing with VOYAGER-PAD.

What we're looking for on the benefit side is a therapy that can improve patency of our revascularization procedures; that can improve our long-term outcomes; and reduce also, as an additive, global cardiovascular events. We're also looking for one where there is minimal additional risk associated with these agents; that there's no other off-target adverse events; and also, ideally, that this works synergistically with our antiplatelet therapy.

The VOYAGER-PAD study was a unique study involving more than 6500 patients with symptomatic lower extremity PAD. This included patients who were undergoing a procedure, either endovascularly or surgically, to revascularize their legs. Everybody had aspirin 100 mg daily, and then they were randomly assigned after their procedure to either rivaroxaban 2.5 mg twice a day vs placebo. Clopidogrel was able to be used at the opinion of the operator, so at their discretion. It was not randomized into one arm or the other. It was followed and I'll show you the results for patients who were treated with clopidogrel in addition to this program vs not. The primary efficacy endpoint included both limb events and cardiovascular events; it was a composite endpoint of acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding.

I just want to highlight, out of the patients randomly assigned in this trial, about 25% had critical limb ischemia and the other 75% had claudication. About one-third underwent a surgical approach and two-thirds underwent an endovascular approach.

In the primary results, looking at the composite endpoint that combined both limb events and cardiovascular events, we can see that over a follow-up of up to 3 years, that there was a 15% reduction in the hazard of the primary endpoint if patients were treated with rivaroxaban plus aspirin vs placebo plus aspirin. You can see here though, the hazard ratio is slightly above one, suggesting a potential signal. There was no statistically significant increase in TIMI major bleeding when rivaroxaban 2.5 mg twice a day was added to aspirin in comparison to aspirin alone after a revascularization procedure.

When we break down that bleeding signal a little bit more, we can look at what's important to many of us who do these procedures, peri-procedural bleeding. You can see on the left here that after starting the 2.5 mg twice a day of rivaroxaban, there was no significant increase in post-procedural bleeding, particularly requiring patients to go back to the operating room. On the right side here, we can see that, similarly, there was no increase in any post-procedure bleeding for any revascularization approach.

What about clopidogrel? As I mentioned before, operators were allowed to use clopidogrel at their discretion in addition to either aspirin plus rivaroxaban 2.5 mg twice a day in purple, vs the placebo plus aspirin in red. On the left side here, we can see that even when clopidogrel was used in about 3,300 patients, there was no significant difference in the signal of efficacy with the rivaroxaban 2.5 mg twice a day. In the safety outcome, no significant difference in that safety endpoint of major bleeding. On the right side here is the patients without clopidogrel. We can see that same preservation of the efficacy endpoint irrespective of clopidogrel, so here without clopidogrel, and that same signal of safety for the primary safety outcome.

I'll end this section by just highlighting the fact that for every patient who was treated with rivaroxaban 2.5 mg twice a day as part of the revascularization strategy, you can reduce 181 events per 10,000 patients treated at one year, with only a 29-person increased risk of a primary safety event, in this case, TIMI major bleeding.

We took an opportunity to look at some of our prior data in this space, both in the anticoagulants as well as antiplatelet therapy. What we can conclude from the available data that existed prior to VOYAGER-PAD, is that both oral anticoagulants, in particular warfarin and/or DAPT, leads to increased bleeding with no clear benefit or improvement in patency or long term limb outcomes. Again, this finding was consistent for both endovascular and surgical revascularization approaches. Conversely, when we think about the dual pathway inhibition with both aspirin antiplatelet therapy and rivaroxaban anticoagulant therapy at the lower 2.5 mg twice a day dose, we found a significant improvement in both limb outcomes as well as a reduction in long term cardiovascular events, without an increase in major bleeding. This was the primary results of the VOYAGER-PAD study and I think should be considered in all of our practices for patients being referred and treated with revascularization procedures. Thank you for the opportunity to present on this section today.

Dr Aronow: Hi, I'm Herb Aronow, and I'd like to welcome you to this segment entitled, "Integration of New Treatment Strategies in PAD Management: Current and Future Directions." Current guidelines are limited in that they don't include the latest randomized controlled trial data on antithrombotic therapy for patients with PAD. Updated guidelines are forthcoming, however. In the next few minutes, I'll review how one might select patients for dual pathway inhibition (DPI) following lower extremity revascularization, including: What factors do you consider when selecting an antithrombotic agent? When is DPI appropriate or inappropriate? What other antithrombotic therapies could or should be considered? What is still unknown about the most appropriate use of the antithrombotic therapy, such as DPI in patients post-lower extremity revascularization?

I'd like to recap some of the data you've already seen presented by Dr Secemsky, specifically the data from the randomized VOYAGER-PAD trial. I want to highlight the fact that there was a 2.6% absolute risk reduction. That would translate into a number needed to treat of ~25 patients to present one of their composite primary endpoint events, namely composite acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. Importantly, secondary endpoints, such as acute limb ischemia and even unplanned limb revascularization for recurrent limb ischemia were also substantially reduced. On balance, the safety profile was excellent. In fact, the primary safety endpoint was not significantly different between the two treatment groups, those who received dual pathway inhibition, and those who received aspirin alone.

One of the common dilemmas that we'll face after a patient is revascularized for lower extremity PAD is how to manage an additional antiplatelet agent, often clopidogrel. There was a very important substudy that Dr Secemsky shared data from, conducted by Will Hiatt and colleagues, where they examined half of the study participants, roughly, who were on clopidogrel, and compared them to the half that were not over the course of the trial. Interestingly, what they found was that the efficacy of dual pathway inhibition, when compared with low-dose aspirin alone, was no different if clopidogrel was added to the mix. Similarly, and importantly, the primary safety endpoint looked no different among patients who also took clopidogrel than among those that did not throughout the trial.

One important observation that was made from Dr Hiatt's substudy was that the duration of clopidogrel was very important. You may remember that patients in VOYAGER-PAD were allowed to be on clopidogrel in addition to their randomized or assigned treatment regimen for up to 6 months; that is, they could have an intended duration of up to 6 months. What they observed was that a proportion were on no clopidogrel, another on clopidogrel for up to 30 days, and a final group on clopidogrel for some time between 30 days and 6 months. In the no-clopidogrel group and the group that was on clopidogrel for up to 1 month, there was no difference in bleeding rates. Interestingly, ISTH major bleeding, which was not the primary, but a secondary safety endpoint in the trial, was substantially increased in those that were on clopidogrel for some time between 30 days and 6 months. Longer durations were associated with an increase in secondary endpoint bleeding, something that's worth taking into consideration when prescribing clopidogrel along with dual pathway inhibition.

I would sum up as follows. Based on the VOYAGER-PAD findings, dual pathway inhibition should be considered in patients who've undergone recent revascularization for femoral-popliteal PAD and who have Rutherford Class 3 to 5 symptoms. Bear in mind, the following groups were excluded from that study, and in those patients, it's possible that the risk might outweigh the benefit -- those at high bleeding risk, such as those on oral anticoagulants for atrial fibrillation, those who've had a prior major bleeding episode, or have a bleeding diathesis. Similarly, patients in whom there was a planned duration of dual antiplatelet therapy that was for greater than 6 months, they were excluded. Therefore, we don't know what the risk-benefit ratio is in that subset of patients. Finally, those who have a history or had a history of ischemic stroke or transient ischemic attack (TIA) or any history of intracranial hemorrhage were excluded. We don't know the risk-benefit balance in that subset. Further study will be necessary to ascertain whether similar safety and efficacy can be ascribed to dual pathway inhibition in the setting of aortoiliac disease, and in patients with major tissue loss or Rutherford Class 6, because those patients were also excluded from the study.

I'd like to thank Jeffrey and Eric for their insights today. Thank you for participating this activity. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.