Making sense of the guidelines: Conserving the benefits of revascularization in your patients with PAD
Consider the following fictional patient case:
- Louisa is 77 years old and lives with her husband and their cat on the outskirts of a city
- She has been enjoying retirement following a long career in the police force and regularly meets her friends for coffee and a catch-up
- One year ago, Louisa began to feel pain in her legs whenever she walked for over 10 minutes. She was diagnosed with peripheral artery disease (PAD) and underwent endovascular revascularization one year ago
- Following the procedure, she began a treatment regimen of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 1 month, followed by single antiplatelet therapy (SAPT) with aspirin
- While she was reassured that her PAD had been treated, Louisa’s doctor informed her of the high risk of having to undergo another procedure, or even amputation
Having just become a grandmother for the second time, Louisa wants to ensure that she will still be able to play with her grandchildren in the future. How can you help to conserve the benefits of her revascularization?
What is the evidence for standard post-revascularization antithrombotic therapy?
Until recently, guideline recommendations to protect patients from thrombotic events following surgical or endovascular revascularization included SAPT with aspirin or clopidogrel, DAPT with both drugs or the use of vitamin K antagonists.1,2 However, many of these recommendations carry a level of evidence C, reflecting a lack of robust evidence to support clinical decision making, or level of evidence B, indicating data derived from a single randomized clinical trial or large non-randomized studies.1,2 Furthermore, these guideline recommendations are typically extrapolated from clinical data in coronary revascularization.2,3
Recommendations for antithrombotic therapy following revascularization in previous guidelines are based on limited evidence, typically based on clinical data from coronary revascularization trials1-3
LoE, level of evidence; PAD, peripheral artery disease
Despite the use of these therapies, patients with PAD remain at high risk of major adverse limb and cardiovascular (CV) events. Cardiologist and vascular medicine specialist Dr Marc Bonaca from the University of Colorado, USA, noted in an interview: ‘Even with known therapies such as aspirin, statins, P2Y12 inhibitors, ACE [angiotensin-converting enzyme] inhibitors…rates of major adverse cardiovascular and limb outcomes are extremely high in this population and particularly after revascularization.’
Dual pathway inhibition can prolong the impact of an intervention and has a reassuring safety profile
The VOYAGER PAD trial aimed to evaluate the efficacy and safety of dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily (bid) plus aspirin 100 mg once daily (od), compared with aspirin alone, to reduce the risk of thrombotic events in patients with PAD undergoing peripheral revascularization procedures.4
The trial involved over 6500 patients and found that patients receiving DPI were significantly better protected from the primary composite efficacy outcome of acute limb ischaemia (ALI), major amputation of vascular aetiology, myocardial infarction, ischaemic stroke or CV death compared with aspirin alone. This benefit did not compromise the risk of major bleeding for patients, with a similar rate of Thrombolysis In Myocardial Infarction (TIMI) bleeding observed in both treatment groups.3
DPI reduced the combined risk of major adverse limb and CV events* following revascularization versus aspirin, with comparable rates of TIMI major bleeding3
*Primary composite efficacy outcome of ALI, major amputation of vascular aetiology, MI, ischaemic stroke or CV death. #A significant increase in the secondary safety outcome of ISTH major bleeding was observed; HR=1.42, 95% CI 1.10–1.84, p=0.007
ALI, acute limb ischaemia; bid, twice daily; CI, confidence interval; CV, cardiovascular; DPI, dual pathway inhibition; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; KM, Kaplan–Meier; MI, myocardial infarction; od, once daily; RRR, relative risk reduction; TIMI, Thrombolysis In Myocardial Infarction
A consistent benefit across different types of major adverse limb and CV events was also demonstrated in patients receiving DPI versus those receiving aspirin alone, including unplanned limb revascularization for recurrent limb ischaemia, hospitalization for coronary or peripheral events, arterial and venous thrombotic events and ALI events.3,5,6 Regardless of your patients’ age, prior critical limb ischaemia, type of revascularization or bypass conduits, or use of clopidogrel, VOYAGER PAD provides reassuring evidence for a consistent effect of DPI with rivaroxaban 2.5 mg bid plus aspirin 100 mg od compared with aspirin alone.7-13
A consistent benefit of DPI versus aspirin in the reduction of major adverse limb and cardiovascular events following revascularization was observed in VOYAGER PAD, in addition to a consistent effect across patient subgroups5-13
ALI, acute limb ischaemia; CI, confidence interval; CLI, critical limb ischaemia; DPI, dual pathway inhibition; HR, hazard ratio
Guidelines now recommend DPI for the prevention of limb and CV events in patients with symptomatic PAD undergoing peripheral revascularization
The findings from VOYAGER PAD have resulted in updates to the European label for rivaroxaban 2.5 mg bid plus aspirin 100 mg od for the prevention of atherothrombotic events in adult patients with symptomatic PAD at high risk of ischaemic events, which has been expanded to include a specific recommendation for patients with a recent lower-extremity revascularization.14
Guidance on DPI use according to the European rivaroxaban label14 DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; PAD peripheral artery disease; TIA, transient ischaemic attack
The promising results from the VOYAGER PAD trial, including results across key patient subgroups, are also reflected in a broad recommendation in the European Atherosclerosis Society/European Society of Vascular Medicine joint statement for therapy in patients with arterial disease: ‘Based on results from the VOYAGER [PAD] study, combination therapy with aspirin (100 mg od) and rivaroxaban (2.5 mg bid) should be considered for DAPT post‑intervention.’15
Moreover, the 2021 European Society of Cardiology expert consensus on antithrombotic therapies in aortic and peripheral arterial diseases states that rivaroxaban 2.5 mg bid plus aspirin 100 mg od should be considered in patients undergoing surgical or endovascular revascularization for lower extremity artery disease, unless there is an obvious concern regarding bleeding; for example, frail or extremely old patients, patients with a history of ischaemic stroke or intracranial haemorrhage who have experienced recent gastrointestinal bleeding or have an estimated glomerular filtration rate <15 ml/min/1.73 m2.16
Looking forward
The consistent results across key patient subgroups provide reassurance that DPI with rivaroxaban 2.5 mg bid plus aspirin 100 mg od is a treatment option with a favourable efficacy and safety profile for many of your patients, like Louisa.
The significance of the results from VOYAGER PAD and the subsequent label update and guideline recommendations for DPI with rivaroxaban 2.5 mg bid and low-dose aspirin was highlighted in the interview with Dr Marc Bonaca. Regarding patients with PAD, he states: ‘even when they’re being revascularized for claudication, they have extremely high rates of acute limb ischaemia and the need for unplanned index revascularizations. That’s where new data from VOYAGER PAD, from rivaroxaban, are so exciting… for the first time we have an agent labelled for preventing these thrombotic vascular events in the setting of revascularization for peripheral artery disease; and rivaroxaban presents a new option in our toolkit to improve outcomes for these patients.’
References
- Aboyans V, Ricco JB, Bartelink MEL et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018;39:763–816. Return to content
- Frank U, Nikol S, Belch J et al. ESVM guideline on peripheral arterial disease. Vasa 2019;48:1–79. Return to content
- Bonaca MP, Bauersachs RM, Anand SS et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994–2004. Return to content
- Capell WH, Bonaca MP, Nehler MR et al. Rationale and design for the vascular outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). Am Heart J 2018;199:83–91. Return to content
- Berkowitz SD, Bauersachs R, Szarek M et al. Prevention of arterial and venous vascular events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone. International Society of Thrombosis and Haemostasis. Virtual, 17–21 July 2021. Oral LB 01.1. Available at: https://isth2021.abstractserver.com/program/#/details/presentations/2660 [accessed 10 January 2022]. Berkowitz SD, Bauersachs R, Szarek M et al. Prevention of arterial and venous vascular events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone. International Society of Thrombosis and Haemostasis. Virtual, 17–21 July 2021. Oral LB 01.1. Available at: https://isth2021.abstractserver.com/program/#/details/presentations/2660 [accessed 10 January 2022]. Return to content
- Hess CN, Debus ES, Nehler MR et al. Reduction in acute limb ischemia with rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization: Insights from VOYAGER PAD. Circulation 2021;144:1831–1841. Return to content
- Bonaca MP, Debus ES, Patel MR et al. Efficacy and safety of rivaroxaban in patients with PAD undergoing lower extremity revascularization for critical limb ischemia. American Heart Association. 13–17 November 2020. Oral Available at: https://cpcclinicalresearch.org/news-and-presentations/ [accessed 10 January 2022]. Bonaca MP, Debus ES, Patel MR et al. Efficacy and safety of rivaroxaban in patients with PAD undergoing lower extremity revascularization for critical limb ischemia. American Heart Association. 13–17 November 2020. Oral Available at: https://cpcclinicalresearch.org/news-and-presentations/ [accessed 10 January 2022]. Return to content
- Debus ES, Nehler MR, Govsyeyev N et al. Effect of rivaroxaban and aspirin in patients with peripheral artery disease undergoing surgical revascularization: Insights from the VOYAGER PAD trial. Circulation 2021;144:1104–1116. Return to content
- Govsyeyev N, Nehler MR, Bauersachs RM et al. Efficacy of rivaroxaban and aspirin in PAD patients with venous and prosthetic surgical bypass conduits: Insights from the VOYAGER PAD trial. Vascular Annual Meeting. San Diego, United States, 18–21 August 2021. Oral [accessed 10 January 2022]. Return to content
- Govsyeyev N, Nehler MR, Debus S et al. Efficacy of rivaroxaban and aspirin in patients with peripheral artery disease with venous and prosthetic surgical bypass conduits: Insights from the VOYAGER PAD trial. J Vasc Surg 2021;74:e24–e25. Return to content
- 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;142:2219–2230. Return to content
- Patel MR, Hiatt WR, Anand SS et al. Rivaroxaban plus aspirin versus aspirin alone after endovascular revascularization for symptomatic PAD: Insights from VOYAGER PAD. American Heart Association. 23–17 November 2020. Oral presentation Available at: https://cpcclinicalresearch.org/news-and-presentations/ [accessed 10 January 2022]. Patel MR, Hiatt WR, Anand SS et al. Rivaroxaban plus aspirin versus aspirin alone after endovascular revascularization for symptomatic PAD: Insights from VOYAGER PAD. American Heart Association. 23–17 November 2020. Oral presentation Available at: https://cpcclinicalresearch.org/news-and-presentations/ [accessed 10 January 2022]. Return to content
- Krantz MJ, Debus SE, Hsia J et al. Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial. Eur Heart J 2021;42:4040–4048. Return to content
- Bayer AG. Xarelto (rivaroxaban) Summary of Product Characteristics. 2021. Available at: https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf [accessed 10 January 2022]. Bayer AG. Xarelto (rivaroxaban) Summary of Product Characteristics. 2021. Available at: https://www.ema.europa.eu/documents/product-information/xarelto-epar-product-information_en.pdf [accessed 10 January 2022]. Return to content
- Belch JJF, Brodmann M, Baumgartner I et al. Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease: European Atherosclerosis Society/European Society of Vascular Medicine Joint Statement. Atherosclerosis 2021;338:55–63. Return to content
- Aboyans V, Bauersachs R, Mazzolai L et al. Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy. Eur Heart J 2021;42:4013–4024. Return to content
See Also
Preserving Limbs And Avoiding Repeat Revascularization In Patients With PAD
See Also
When should dual pathway inhibition be stopped in patients with symptomatic PAD following peripheral revascularization?
See Also
Boosting confidence in preventing recurrent thrombotic events in patients with peripheral artery disease following revascularization
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