Rivaroxaban After Lower-Extremity Revascularization: The VOYAGER PAD Trial
The phase 3 VOYAGER PAD trial demonstrated the benefit of rivaroxaban (Xarelto, Janssen Pharmaceutical Companies of Johnson & Johnson) (2.5 mg twice daily + aspirin 100 mg once daily) in reducing severe vascular events in peripheral artery disease patients after lower-extremity revascularization.1
Dr. Bonaca, can you describe some of the challenges that lower-extremity disease patients face post revascularization?
Historically, lower-extremity revascularization has not experienced as much attention as coronary revascularization. After coronary revascularization, we have a lot of information about the complications that patients can experience. There have been numerous trials looking at new stents, devices, long dual antiplatelet therapy (DAPT), short DAPT, and all sorts of methods of protecting patients after coronary intervention. While very few trials have looked at complications after lower-extremity revascularization, there have been two large recent trials. One is VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) and the other is BEST-CLI (Best Endovascular Versus Best Surgical Therapy in Patients With CLTI). Both trials show that the rate of adverse limb events is extremely high both early and late after revascularization for symptomatic PAD. I think this is not well understood; most people think that acute limb ischemia is rare, but we have learned in these data sets that acute limb ischemia is actually very frequent, including in patients with claudication. Procedural failure requiring an unplanned revascularization of the limb is also extremely frequent. These are highly morbid conditions and it highlights a big unmet need for our patients.
Can you tell us about VOYAGER PAD?
Figure 1 shows the primary results of VOYAGER. Note the primary event rate at the top of the figure for endovascular patients, more than 80% of whom are getting statins and all getting aspirin, and half are getting clopidogrel. The incidence of first — not recurrent, but first — irreversible harm event for the primary endpoint after revascularization was about 20%. There are very few cardiovascular trials with an event rate that high. On the right side of Figure 1, the bar graph shows procedural failure, meaning the patient is coming back with some issue, unplanned, that requires a repeat revascularization, and that number is additive to the 20% of events under the primary endpoint. This is the unmet need, despite best medical therapy, and I don’t think that is well understood.
The purpose of our latest analysis was to further translate the results of the trial. Many interventionalists are thinking, maybe I will use DAPT after my procedure, but then switch to rivaroxaban; maybe rivaroxaban is for chronic disease. People are used to DAPT for stent protection because in coronary revascularization, DAPT was the answer. For the latest pre-specified analysis, we looked at the effect both early, in the first 90 days, and late. We chose the first 90 days because the majority of people who got DAPT were on it for 90 days, or at least most were off by 90 days. Some were on 30 days, 60 days, or the full 90 days, but we wanted to look at that early period.
Figure 2 shows the consistent benefit with rivaroxaban early and late, in that when you look at the bleeding, there is bleeding early and late, but there is a net benefit early and late. The absolute risk reduction is 0.8 and absolute risk increase is 0.3. There is more than a twofold benefit-risk favorable ratio and more than threefold long-term, so that was the first question. But remember, this endpoint includes death, heart attacks, strokes, and other negative outcomes. For the interventionalist or surgeon, what you are worried about is procedural complications: acute limb ischemia and amputation.
Figure 3 shows the net clinical benefit, which includes bleeding and cardiovascular death. It was clearly positive both early and late for rivaroxaban, with a 25% reduction early. One key take-home is that early on, in the first 90 days, there is a very high rate for the combination of acute limb ischemia and major vascular amputation (Figure 4). For rivaroxaban, there is over a 1% absolute risk reduction in 90 days, which is a huge absolute risk reduction for a 90-day outcome, and a 45% relative risk reduction, which is a profound early effect. The curve separates within days.
Now, what the proceduralists want to know is, what about if I am giving DAPT (clopidogrel)? Do I still need rivaroxaban? Or is DAPT enough for 90 days, and then do I transition to rivaroxaban? What we know from an early analysis3 is that DAPT didn’t really matter long-term, looking over 3 years. We do know that longer DAPT is associated with more bleeding. DAPT for more than 30 days shows a threefold excess in bleeding. Whereas, if you shorten DAPT to less than 30 days, you don’t get that excess in rate of bleeding.
Endovascular patients are getting statins, aspirin, and clopidogrel — all of our best therapies — and yet the rates of acute limb ischemia and major amputation are high.3 It looks similar to what we used to see in the first-generation coronary stenting era where we had very high rates of stent thrombosis that people really worried about, which is actually what put DAPT on the map. Yet for lower extremity revascularization patients, despite DAPT, the event rates are very high.
What is the benefit of rivaroxaban in this early period if you are already using DAPT?
When we looked at the effects of added rivaroxaban, we found over a 50% reduction in acute limb ischemia and a combination of acute limb ischemia or amputation within that first 90-day period.2 This is a very robust reduction and benefit in that early period, and tells us DAPT is not enough. It is in contrast to the coronary population where, in coronary disease, DAPT was superior to anticoagulants for stent protection. In the lower extremities, it is not the same, because thrombin is such a key mediator of risk. There are huge vascular territories and a great deal of vascular disruption. DAPT alone doesn’t offer much protection. Figure 5 is a forest plot and shows the benefit of added rivaroxaban. For anything left of the line, rivaroxaban is better. To the right of the line, placebo is better. It doesn’t matter whether you cut the data at 30 days, 90 days, on top of DAPT, on top of aspirin — whatever the endpoint, it is all in favor of starting rivaroxaban early. Those are the key findings.
Can you tell us more about how rivaroxaban works?
Rivaroxaban is a Factor Xa inhibitor and works upstream in the coagulation cascade. One of the key effects of Factor Xa inhibition is how it inhibits thrombin generation. Thrombin is the core of this story because of its many effects. Thrombin is the most potent activator of platelets and also has adverse effects on the vasculature, including the endothelium and vascular smooth muscle cells. Thrombin is a bad actor and is particularly bad in PAD. We actually learned about the effects of thrombin a long time ago, with the study of a drug called vorapaxar. It is not widely used, but vorapaxar is a thrombin inhibitor, with profound benefits in PAD. It was approved in PAD, even though it is not really used because of concerns for bleeding risk. The effect of vorapaxar was our first clue that the pathobiology of adverse limb events is about more than the platelet; it is also about thrombin. There are two pathways: one is the platelet pathway and one is the thrombin pathway. Blocking both pathways reduces risk. If you only focus on platelet inhibition, you don’t interrupt thrombin-mediated risk. There are other ways of interrupting thrombin, such as warfarin, for example, and other drugs, but their bleeding risks have been intolerable. In addition, what we have learned not just from VOYAGER PAD, but also from the ATLAS and COMPASS trials, is that a lower dose works better to interrupt Xa. Use of a lower dose seems counterintuitive, but using 2.5 mg of rivaroxaban is better for both efficacy and safety. Using a full dose of apixaban like in the APPRAISE2 trial on top of DAPT in acute coronary syndrome patients was not beneficial and was associated with a high rate of bleeding. We have found that it is the very low dosage of rivaroxaban, as studied in VOYAGER PAD, that is key, combined with an antiplatelet.
Are there any comorbidities that might affect how patients do with rivaroxaban?
Like all antithrombotics, patients who are at a high risk of bleeding may not be the best candidates for these strategies, and unfortunately, these are some of the sickest patients. Patients who have cancer or patients who require full-dose anticoagulation for atrial fibrillation are not eligible for this strategy or even for DAPT. The 2.5 mg rivaroxaban twice daily plus aspirin 100 mg once daily strategy is for patients who don’t have another indication for full-dose anticoagulation or aren’t at high risk of bleeding. Other than that, in the VOYAGER PAD trial, there was no effect modification by any of the subgroups. Whether patients are older or younger, have diabetes, or whether it is a first revascularization or second, the benefits with rivaroxaban (plus aspirin) are consistent.
What should interventionalists take away from VOYAGER PAD?
We most recently presented the pre-specified analysis at the American College of Cardiology meeting and part of why we wanted to get it out was the debates with some of my interventional colleagues who have said, “DAPT is enough. We don’t need this. Maybe long-term, but this isn’t a procedural drug.” They are really focused on this early period of risk and wanted to see an early benefit.
How we got here is an unusual story, because usually with drugs, we start looking at outcomes in the acute period, then do subsequent trials to understand the long-term benefit. In this case, there were two sister trials, VOYAGER PAD and COMPASS. The intent of COMPASS was to evaluate very long-term outcomes with rivaroxaban in this same population, so it was expected that VOYAGER PAD would conclude first and then the COMPASS trial would report data about long-term outcomes. But COMPASS was actually halted early for overwhelming efficacy because there were reductions in mortality and amputation, so that the COMPASS data came out before VOYAGER PAD data. We do know that in patients with chronic PAD, a long-term rivaroxaban plus aspirin strategy reduces major adverse cardiac events, and has a profound reduction in stroke, a 70% reduction in amputation, and a reduction in mortality.4 The next question ended up being how early to start a rivaroxaban strategy and now we have answered that with the results of the pre-specified analysis.
The key message is that if you are doing procedures on these patients, whether for claudication or chronic limb-threatening ischemia (CLTI), and if you are using aspirin, statins, and DAPT, it is not enough. The rates of adverse events are very high, you should consider rivaroxaban, and consider adding it very early in the days after revascularization, as was done in VOYAGER PAD. Waiting for 90 days to switch to rivaroxaban exposes patients to a high risk of adverse limb events. We need to transform this concept of when to start dual pathway inhibition, just as we do for DAPT after percutaneous coronary intervention. The patient should leave with a bag of aspirin and rivaroxaban because that is actually the most important thing to prevent the early complications of the intervention.
Has there been an economic benefit from the use of rivaroxaban?
Yes. Rivaroxaban is the first drug to ever be approved for amputation and acute limb ischemia, so there was a cost analysis.5,6 It is interesting that the most expensive events that occurred in VOYAGER PAD were acute limb ischemia, amputation, and peripheral revascularization, and that these events were much more expensive than heart attack or stroke. There is also an enormous number of events.7 In VOYAGER PAD, total vascular events under the primary endpoint was 1100 events, and out of 6500 patients, there were 4200 total events. Now, anyone who sees these patients will tell you there is never one event. Our patients keep coming back and there are frequent complications. If you translate that into an economic analysis, a preventive strategy does result in a cost savings, because these are the most costly events that occur in this population.
What are future plans for VOYAGER PAD?
There are ongoing analyses looking at specific subgroups and other aspects. For example, we know a great deal about coronary anatomy and how it drives risk. We have the SYNTAX score, and have learned that someone with 3-vessel disease does worse than someone with single-vessel disease or left main disease. However, we still don’t know how to correlate anatomy with outcomes for lower-extremity PAD. We are developing that body of data out of VOYAGER PAD, utilizing a large angiographic core lab. It will help us better understand risk in patients with PAD and how to treat them. We are also looking at predictors of bleeding. In the coronary field, we exclude those at high risk of bleeding and then use more potent strategies, and this has been codified in the guidelines. We don’t yet know how to do that in PAD. Some of the bleeding risk factors may be the same as for coronary disease, but lower-extremity bleeding risk factors could also be different, so we are looking at these factors as well. There are a number of other analyses looking at benefit-risk in different ways and for different procedural approaches. Under review right now is an analysis looking at those patients who underwent endovascular treatment. We published the surgical and graft data.8 There is a lot more analysis to come that will help us better understand the treatment of lower-extremity disease overall, not simply around rivaroxaban. The field of acute PAD intervention and how we understand risks, select patients, and treat them, is still open for future trials.
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The VOYAGER PAD Clinical Trial1
The global, randomized, double-blind Phase 3 VOYAGER PAD study included 6564 patients. Patients were randomized in a 1:1 ratio and received either rivaroxaban (2.5 mg twice daily) + aspirin (100 mg once daily) (n=3286) or aspirin alone (100 mg once daily) (n=3278). Patients were stratified by revascularization procedure (endovascular versus surgical) and use of clopidogrel, administered at the treating physician’s discretion.
Patients were followed for a median of 28 months. The primary efficacy endpoint was a composite of major adverse limb and cardiovascular events, including acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular-related mortality. The principal safety endpoint was major bleeding according to the TIMI classification.
Eligible patients were at least 50 years old with documented symptomatic lower-extremity peripheral artery disease (PAD). Patients were eligible after a successful revascularization for symptomatic PAD within the last 10 days. Approximately two-thirds were treated with an endovascular procedure (65%) and one-third were treated surgically (35%). The median age was 67 years and 26% were women. Common risk factors included diabetes, an estimated glomerular filtration rate <60 mL/min/1.73 m2 (mild-to-moderate kidney disease), and current smokers.
Patients were excluded if they were clinically unstable, at heightened bleeding risk, or needed prohibited concomitant medications, including long-term clopidogrel.
Nearly 1 in 5 patients taking antiplatelet therapy alone suffered a major adverse limb or cardiovascular event, but this risk was reduced by 15% when rivaroxaban was added. The Kaplan-Meier (KM) estimates of the incidence at 3 years for rivaroxaban/aspirin compared to aspirin alone were 17.3% vs 19.9%, respectively (hazard ratio [HR]=0.85; 95% confidence interval [CI], 0.76-0.96; P=.009). The benefit of adding rivaroxaban to aspirin was apparent early, was consistent among major subgroups and continued to accrue over time.
The principal safety endpoint was met, with no significant increase in TIMI major bleeding in patients treated with rivaroxaban plus aspirin compared to aspirin alone. The Kaplan-Meier estimates of the incidence at 3 years for rivaroxaban/aspirin compared to aspirin alone were 2.65% vs 1.87%, respectively (HR=1.43; 95% CI, 0.97-2.10; P=.07). There were numerically fewer intracranial bleeding events in the rivaroxaban/aspirin group (0.60% vs 0.90%; HR=0.78; 95% CI, 0.38-1.61) and no increase in fatal bleeding (0.21% vs 0.21%; HR=1.02; 95% CI, 0.33-3.15) across both groups.
Disclosures: VOYAGER PAD funded through grants from Bayer and Janssen to CPC Clinical Research. Dr. Bonaca reports he is the Executive Director of CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from: Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol-Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, Yale Cardiovascular Research Group. Dr. Bonaca also reports stock in Medtronic and Pfizer and consulting fees from Audentes.
References
1. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020 May 21;3 82(21): 1994-2004. doi: 10.1056/NEJMoa2000052
2. New VOYAGER PAD analysis confirms consistent benefit of Xarelto (rivaroxaban) plus aspirin following lower extremity revascularization (LER). News release. Janssen. March 5, 2023. Accessed March 7, 2023. https://www.jnj.com/new-voyager-pad-analysis-confirms-consistent-benefit-of-xarelto-rivaroxaban-plus-aspirin-following-lower-extremity-revascularization-ler
3. Hiatt WR, Bonaca MP, Patel MR, et al. Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety. Circulation. 2020 Dec 8;142(23):2219-2230. doi:10.1161/CIRCULATIONAHA.120.050465
4. Bauersachs RM, Szarek M, Brodmann M, et al; VOYAGER PAD Committees and Investigators. Total ischemic event reduction with rivaroxaban after peripheral arterial revascularization in the VOYAGER PAD trial. J Am Coll Cardiol. 2021 Jul 27; 78(4): 317-326. doi:10.1016/j.jacc.2021.05.003
5. Cowie MR, Lamy A, Levy P, et al. Health economic evaluation of rivaroxaban in the treatment of patients with chronic coronary artery disease or peripheral artery disease. Cardiovasc Res. 2020 Sep 1; 116(11): 1918-1924. doi:10.1093/cvr/cvz278
6. Spoorendonk JA, Briere JB, Bowrin K, et al. Clinical implications and cost-effectiveness analysis of rivaroxaban in patients with coronary artery disease or peripheral arterial disease in the Netherlands. J Med Econ. 2021 Jan-Dec;24(1): 1231-1239. doi:10.1080/13696998.2021.1997024
7. Desai U, Kharat A, Hess CN, Milentijevic D, Laliberté F, Zuckerman P, Benson J, Lefebvre P, Hiatt WR, Bonaca MP. Incidence of major atherothrombotic vascular events among patients with peripheral artery disease after revascularization. Ann Vasc Surg. 2021 Aug; 75: 217-226. doi:10.1016/j.avsg.2021.02.025
8. Bonaca MP, Szarek M, Debus ES, et al. Efficacy and safety of rivaroxaban versus placebo after lower extremity bypass surgery: A post hoc analysis of a “CASPAR like” outcome from VOYAGER PAD. Clin Cardiol. 2022 Dec; 45(12): 1143-1146. doi:10.1002/clc.23926
