Signifi cance of the choice of antithrombotic therapy for a patient after revascularization of lower limbs in a long-term perspective (literature review)

• Fokin A.A.
• Shaldina M.V.

Abstract

Occlusive disease of lower limb arteries is one of manifestations of systemic atherosclerosis. In this pathology, the probability of systemic complications combined with acute or progressive chronic ischemia of lower limbs is extremely high. The number of open and endovascular operations in occlusion of arteries below the inguinal ligament is constantly growing, but even a successfully performed restorative operation decreases only the threat of limb loss and cannot influence progression of the disease or diminish the risk of ischemic complications. The VOYAGER PAD randomized international double-blind, placebo-controlled trial studying the profile of efficacy and safety of rivaroxaban at a dose of 2.5 mg twice daily added to conventional therapy with acetylsalicylic acid or to dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) demonstrated the capability of combined antithrombotic therapy to improve the results of surgical treatment of patients with lower limb artery pathology.

The VOYAGER PAD trial showed that patients receiving combined therapy with rivaroxaban at a dose of 2.5 mg twice daily + acetylsalicylic acid 100 mg/day had a significantly lower risk for the development of acute limb ischemia, major amputation, myocardial infarction and cardiovascular death as compared with those taking therapy with acetylsalicylic acid alone (HR 0.85; 95% CI 0.76–0.96; p=0.0085). The frequency of major hemorrhage did not significantly differ between the groups (HR 1.43; 95% CD 0.97–2.10; p=0.07).

Thus, the choice of pathogenetically substantiated antithrombotic therapy inhibiting both links of thrombus formation in patients after endured revascularization of lower limbs may help preserve patency of the reconstructed zone, decrease the risk of limb loss and systemic thrombotic complications in a long-term perspective.

Keywords:atherosclerosis of lower extremity arteries; lower limb revascularization; lower limb amputation; repeat interventions on lower-limb arteries; antithrombotic therapy; risk of hemorrhage; rivaroxaban

References

1. Zipes D.P., Libby P., Bonow R.O., et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Single Volume, 11th Edition. 2018; 2040.

2. Fritidge R. Mechanisms of Vascular Disease: A Textbook for Vascular Specialists. Springer International Publishing; 3^rd ed. 2020; 755. DOI: https://doi.org/10.1007/978-3-030-43683-4

3. Bokeriya L.A., Milievskaya E.B., Pryanishnikov V.V., et al. Diseases and congenital anomalies of the circulatory system. Cardiovascular surgery – 2020. Moscow: NMIC SSKH im. A.N. Bakuleva Minzdrava Rossii. 2021; 294. (in Russian)

4. Anand S.S., Caron F., Eikelboom J.W., et al. Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial. Journal of the American College of Cardiology. 2018; 71 (20): 2306–2315. DOI: https://doi.org/10.1016/j.jacc.2018.03.008

5. Creager M.A., Matsushita K., Arya S., et al. Reducing Nontraumatic Lower-Extremity Amputations by 20% by 2030: Time to Get to Our Feet: A Policy Statement From the American Heart Association. Circulation. 2021; 143: 875–891. DOI: https://doi.org/10.1161/CIR.0000000000000967

6. Pokrovskiy A.V., Golovyuk A.L. The state of vascular surgery in the Russian Federation in 2018. Angiology and Vascular Surgery. 2019; 25 (Issue 2): 48. (in Russian)

7. Mahoney E.M., Wang K., Keo H.H., et al. Vascular Hospitalization Rates and Costs in Patients With Peripheral Artery Disease in the United States. Circulation: Cardiovascular Quality and Outcomes. 2010; 3 (6): 642–651. DOI: https://doi.org/10.1161/CIRCOUTCOMES.109.930735

8. Baumgartner I., Norgren L., Fowkes F.G.R., et al. Executive Committee and Investigators of the EUCLID Trial. Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical Revascularization: The EUCLID Trial. Journal of the American College of Cardiology. 2018; 72 (14): 1563–1572. DOI: https://doi.org/10.1016/j.jacc.2018.07.046

9. Hess C.N., Huang Z., Patel M.R., et al. Acute Limb Ischemia in Peripheral Artery Disease. Circulation. 2019; 140 (7): 556–565. DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.039773

10. Bonaca M.P., Gutierrez J.A., Creager M.A., et al. Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50). Circulation. 2016; 133 (10): 997–1005. DOI: https://doi.org/10.1161/CIRCULATIONAHA.115.019355

11. Narula N., Dannenberg A.J., Olin J.W., et al. Pathology of Peripheral Artery Disease in Patients With Critical Limb Ischemia. Journal of the American College of Cardiology. 2018; 72 (18): 2152–2163. DOI: https://doi.org/10.1016/j.jacc.2018.08.002

12. Eikelboom J.W., Bhatt D.L., Fox K.A.A., et al. Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease. Journal of the American College of Cardiology. 2021; 78 (1): 14–23. DOI: https://doi.org/10.1016/j.jacc.2021.04.083.

13. Conte M.S., Bradbury A.W., Kolh P., et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Clinical practice guideline document. 2019; 69 (6S): 3S–125S. DOI: https://doi.org/10.1016/j.jvs.2019.02.016.

14. Bokeriya L.A., Pokrovskiy A.V., Akchurin R.S., et al. National guidelines for the diagnosis and treatment of diseases of the arteries of the lower extremities. Angiology and Vascular Surgery. 2019; 25 (Supl. 2): 89. (in Russian)

15. Debus E.S., Nehler M.R., Fanelli F. The Voyager PAD Trial New Path for Post-revascularisation PAD Patients. European Journal of Vascular and Endovascular Surgery. 2020; 59 (5): 699–700. DOI: https://doi.org/10.1016/j.ejvs.2020.03.041

16. Debus E.S., Nehler M.R., Hiatt W.R., et al. Reply to “The VOYAGER PAD Trial in Surgical Perspective: A Debate”. European Journal of Vascular and Endovascular Surgery. 2021; 61 (5): 723–724. DOI: https://doi.org/10.1016/j.ejvs.2021.02.051

17. Bonaca M.P., Bauersachs R.M., Anand S.S., et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. New England Journal of Medicine. 2020; 382 (21): 1994–2004. DOI: https://doi.org/10.1056/NEJMoa2000052

18. Bauersachs R.M., 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. Journal of the American College of Cardiology. 2021; 78 (4): 317–326. DOI: https://doi.org/10.1016/j.jacc.2021.05.003

19. Hussain M.A., Al-Omran M., Creager M.A., et al. Antithrombotic Therapy for Peripheral Artery Disease: Recent Advances. Journal of the American College of Cardiology. 2018; 71 (21): 2450–2467. DOI: https://doi.org/10.1016/j.jacc.2018.03.483

20. Anand S.S., Bosch J., Eikelboom J.W., et al. COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018; 391(10117): 219–229. DOI: https://doi.org/10.1016/S0140-6736(17)32409-1

21. Kearon C., Akl E.A., Ornelas J., et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016; 149 (2): 315–352. DOI: https://doi.org/10.1016/j.chest.2015.11.026

22. Hindricks G., Potpara T., Dagres N., et al. ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal. 2021; 42 (5): 373–498. DOI: https://doi.org/10.1093/eurheartj/ehaa612

23. Krantz M.J., Debus S.E., 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. European Heart Journal. 2021; 42 (39): 4040–4048. DOI: https://doi.org/10.1093/eurheartj/ehab408

24. Hsia J., Szarek M., Anand S., et al. Rivaroxaban in Patients With Recent Peripheral Artery Revascularization and Renal Impairment: The VOYAGER PAD Trial. Journal of the American College of Cardiology. 2021; 78 (7): 757–759. DOI: https://doi.org/10.1016/j.jacc.2021.06.021

25. Bonaca M.P., Bauersachs R.M., Patel M.R., et al. ACC. USA: Chicago. 28–30 March 2020; 402–410. https://cpcclinicalresearch.org/wp-content/uploads/2020/03/CPC-VOYAGER-PAD-Primary-Results-Slide-Presentation-by-Marc-P.-Bonaca.pdf.

26. Kaplovitch E., Eikelboom J.W., Dyal L., et al. Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial. JAMA Cardiology. 2021; 6 (1): 21–29. DOI: https://doi.org/10.1001/jamacardio.2020.4390

27. 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. European Heart Journal. 2021; 42 (39): 4013–4024. DOI: https://doi.org/10.1093/eurheartj/ehab390