Efficacy and Safety of Apixaban in Reducing Restenosis and Limb Loss in PAD Patients.

Summary

This study will evaluate the efficacy and safety of apixaban 2.5 mg twice daily plus aspirin compared to the standard treatment (clopidogrel plus aspirin) in patients with critical limb ischemia undergoing infrapopliteal arterial endovascular intervention.

Timeline

Start

2020-01-09

Primary completion

2022-02-02

Completion

2022-05-02

Publications

• Background Ferraresi R, Centola M, Ferlini M, Da Ros R, Caravaggi C, Assaloni R, Sganzaroli A, Pomidossi G, Bonanomi C, Danzi GB. Long-term outcomes after angioplasty of isolated, below-the-knee arteries in diabetic patients with critical limb ischaemia. Eur J Vasc Endovasc Surg. 2009 Mar;37(3):336-42. doi: 10.1016/j.ejvs.2008.12.001. Epub 2008 Dec 27.
• Background Tsetis D, Belli AM. The role of infrapopliteal angioplasty. Br J Radiol. 2004 Dec;77(924):1007-15. doi: 10.1259/bjr/97382129.
• Background Shishehbor MH, Hammad TA, Zeller T, Baumgartner I, Scheinert D, Rocha-Singh KJ. An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia. J Vasc Surg. 2016 May;63(5):1311-7. doi: 10.1016/j.jvs.2015.11.042. Epub 2016 Feb 6.
• Background El-Sayed H, Bennett ME, Loh TM, Davies MG. Retrograde Pedal Access and Endovascular Revascularization: A Safe and Effective Technique for High-Risk Patients with Complex Tibial Vessel Disease. Ann Vasc Surg. 2016 Feb;31:91-8. doi: 10.1016/j.avsg.2015.09.015. Epub 2015 Nov 26.
• Background Wu R, Yao C, Wang S, Xu X, Wang M, Li Z, Wang S. Percutaneous transluminal angioplasty versus primary stenting in infrapopliteal arterial disease: a meta-analysis of randomized trials. J Vasc Surg. 2014 Jun;59(6):1711-20. doi: 10.1016/j.jvs.2014.03.012.
• Background Silingardi R, Tasselli S, Cataldi V, Moratto R, Gennai S, Coppi G, Marcheselli L, Coppi G. Bifurcated coronary stents for infrapopliteal angioplasty in critical limb ischemia. J Vasc Surg. 2013 Apr;57(4):1006-13. doi: 10.1016/j.jvs.2012.09.080. Epub 2013 Jan 21.
• Background Gutzeit A, Schoch E, Sautter T, Jenelten R, Graf N, Binkert CA. Antegrade access to the superficial femoral artery with ultrasound guidance: feasibility and safety. J Vasc Interv Radiol. 2010 Oct;21(10):1495-500. doi: 10.1016/j.jvir.2010.03.021.
• Background Marcus AJ, Lotzof K, Howard A. Access to the superficial femoral artery in the presence of a "hostile groin": a prospective study. Cardiovasc Intervent Radiol. 2007 May-Jun;30(3):351-4. doi: 10.1007/s00270-005-0347-y.
• Background Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation. 2013 Aug 6;128(6):615-21. doi: 10.1161/CIRCULATIONAHA.113.001811.
• Background Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5.
• Background Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008 May;47(5):975-981. doi: 10.1016/j.jvs.2008.01.005. Epub 2008 Apr 18.
• Background Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, Fusaro M, Gabrielli L, Losa S, Stella A, Gargiulo M, Mantero M, Caminiti M, Ninkovic S, Curci V, Morabito A. Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg. 2005 Jun;29(6):620-7. doi: 10.1016/j.ejvs.2005.02.035. Epub 2005 Mar 28.
• Background Nair V, Chaisson G, Abben R. Strategies in infrapopliteal intervention: improving outcomes in challenging patients. J Interv Cardiol. 2009 Feb;22(1):27-36. doi: 10.1111/j.1540-8183.2008.00412.x. No abstract available.
• Background Sumpio BE, Forsythe RO, Ziegler KR, van Baal JG, Lepantalo MJ, Hinchliffe RJ. Clinical implications of the angiosome model in peripheral vascular disease. J Vasc Surg. 2013 Sep;58(3):814-26. doi: 10.1016/j.jvs.2013.06.056.
• Background Sadaghianloo N, Jean-Baptiste E, Declemy S, Mousnier A, Brizzi S, Hassen-Khodja R. Percutaneous angioplasty of long tibial occlusions in critical limb ischemia. Ann Vasc Surg. 2013 Oct;27(7):894-903. doi: 10.1016/j.avsg.2013.02.008.
• Background Singh GD, Armstrong EJ, Yeo KK, Singh S, Westin GG, Pevec WC, Dawson DL, Laird JR. Endovascular recanalization of infrapopliteal occlusions in patients with critical limb ischemia. J Vasc Surg. 2014 May;59(5):1300-7. doi: 10.1016/j.jvs.2013.11.061. Epub 2014 Jan 3.
• Background Saqib NU, Domenick N, Cho JS, Marone L, Leers S, Makaroun MS, Chaer RA. Predictors and outcomes of restenosis following tibial artery endovascular interventions for critical limb ischemia. J Vasc Surg. 2013 Mar;57(3):692-9. doi: 10.1016/j.jvs.2012.08.115. Epub 2013 Jan 23.
• Background Scheinert D, Ulrich M, Scheinert S, Sax J, Braunlich S, Biamino G. Comparison of sirolimus-eluting vs. bare-metal stents for the treatment of infrapopliteal obstructions. EuroIntervention. 2006 Aug;2(2):169-74.
• Background Silingardi R, Lauricella A, Coppi G, Chester J, Trevisi-Borsari G, Corvi V, Marcheselli L, Coppi G. Durability and efficacy of tibial arterial stent placement for critical limb ischemia. J Vasc Interv Radiol. 2015 Apr;26(4):475-83.e2. doi: 10.1016/j.jvir.2014.11.044. Epub 2015 Feb 7.
• Background Ozkan U, Oguzkurt L, Tercan F. Atherosclerotic risk factors and segmental distribution in symptomatic peripheral artery disease. J Vasc Interv Radiol. 2009 Apr;20(4):437-41. doi: 10.1016/j.jvir.2009.01.010.
• Background Bolia A, Brennan J, Bell PR. Recanalisation of femoro-popliteal occlusions: improving success rate by subintimal recanalisation. Clin Radiol. 1989 May;40(3):325. doi: 10.1016/s0009-9260(89)80231-4. No abstract available.
• Background Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg. 2000 Jan;31(1 Pt 2):S1-S296. No abstract available.
• Background Kawarada O, Yokoi Y, Higashimori A, Waratani N, Waseda K, Honda Y, Fitzgerald PJ. Stent-assisted below-the-ankle angioplasty for limb salvage. J Endovasc Ther. 2011 Feb;18(1):32-42. doi: 10.1583/10-3214.1.
• Background Kawarada O, Yasuda S, Nishimura K, Sakamoto S, Noguchi M, Takahi Y, Harada K, Ishihara M, Ogawa H. Effect of single tibial artery revascularization on microcirculation in the setting of critical limb ischemia. Circ Cardiovasc Interv. 2014 Oct;7(5):684-91. doi: 10.1161/CIRCINTERVENTIONS.113.001311. Epub 2014 Aug 19.
• Background Peeters Weem SM, van Haelst ST, den Ruijter HM, Moll FL, de Borst GJ. Lack of Evidence for Dual Antiplatelet Therapy after Endovascular Arterial Procedures: A Meta-analysis. Eur J Vasc Endovasc Surg. 2016 Aug;52(2):253-62. doi: 10.1016/j.ejvs.2016.04.023. Epub 2016 May 27.
• Background Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. 2006 Mar 21;113(11):e463-654. doi: 10.1161/CIRCULATIONAHA.106.174526. No abstract available.
• Background Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007 Jan;45 Suppl S:S5-67. doi: 10.1016/j.jvs.2006.12.037. No abstract available.
• Background Alonso-Coello P, Bellmunt S, McGorrian C, Anand SS, Guzman R, Criqui MH, Akl EA, Vandvik PO, Lansberg MG, Guyatt GH, Spencer FA. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e669S-e690S. doi: 10.1378/chest.11-2307.
• Background European Stroke Organisation; Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, Heras M, Kownator S, Minar E, Ostergren J, Poldermans D, Riambau V, Roffi M, Rother J, Sievert H, van Sambeek M, Zeller T; ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011 Nov;32(22):2851-906. doi: 10.1093/eurheartj/ehr211. Epub 2011 Aug 26. No abstract available.
• Background Yen HT, Hsieh MJ, Wu CC, Lee FY. Effect of systemic urokinase infusion after lower limb percutaneous transluminal angioplasty on limb salvage rate in patients with late-stage critical limb ischemia. Eur J Vasc Endovasc Surg. 2014 Oct;48(4):414-22. doi: 10.1016/j.ejvs.2014.04.006. Epub 2014 Jun 28.
• Background Dosluoglu HH, Harris LM. Endovascular management of subacute lower extremity ischemia. Semin Vasc Surg. 2008 Dec;21(4):167-79. doi: 10.1053/j.semvascsurg.2008.11.002.
• Background Lam RC, Shah S, Faries PL, McKinsey JF, Kent KC, Morrissey NJ. Incidence and clinical significance of distal embolization during percutaneous interventions involving the superficial femoral artery. J Vasc Surg. 2007 Dec;46(6):1155-9. doi: 10.1016/j.jvs.2007.07.058.
• Background Motarjeme A, Gordon GI, Bodenhagen K. Thrombolysis and angioplasty of chronic iliac artery occlusions. J Vasc Interv Radiol. 1995 Nov-Dec;6(6 Pt 2 Suppl):66S-72S. doi: 10.1016/s1051-0443(95)71251-9.
• Background Wholey MH, Maynar MA, Wholey MH, Pulido-Duque JM, Reyes R, Jarmolowski CR, Castaneda WR. Comparison of thrombolytic therapy of lower-extremity acute, subacute, and chronic arterial occlusions. Cathet Cardiovasc Diagn. 1998 Jun;44(2):159-69. doi: 10.1002/(sici)1097-0304(199806)44:23.0.co;2-5.
• Background Lee HF, Chan YH, Wang CL. Using Rivaroxaban as Thrombolytic Treatment for a Patient of Pedal Arch Arterial Thrombosis with Suboptimal Result of Endovascular Therapy. Acta Cardiol Sin. 2016 Sep;32(5):623-626. doi: 10.6515/acs20151229a.
• Background Undas A, Ariens RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):e88-99. doi: 10.1161/ATVBAHA.111.230631. Epub 2011 Aug 11.
• Background Warfarin Antiplatelet Vascular Evaluation Trial Investigators; Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, Sussex B, Liu L, Guzman R, Cina C, Crowell R, Keltai M, Gosselin G. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-27. doi: 10.1056/NEJMoa065959.
• Background Greig SL, Garnock-Jones KP. Apixaban: A Review in Venous Thromboembolism. Drugs. 2016 Oct;76(15):1493-1504. doi: 10.1007/s40265-016-0644-6.
• Background Beyer-Westendorf J, Lensing AW, Arya R, Bounameaux H, Cohen AT, Wells PS, Middeldorp S, Verhamme P, Hughes R, Kucher N, Pap AF, Trajanovic M, Prins MH, Prandoni P, Weitz JI. Choosing wisely: The impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials. Thromb Res. 2017 Jan;149:29-37. doi: 10.1016/j.thromres.2016.11.014. Epub 2016 Nov 21.
• Background Bleker SM, Cohen AT, Buller HR, Agnelli G, Gallus AS, Raskob GE, Weitz JI, Curto M, Sisson M, Middeldorp S. Clinical presentation and course of bleeding events in patients with venous thromboembolism, treated with apixaban or enoxaparin and warfarin. Results from the AMPLIFY trial. Thromb Haemost. 2016 Nov 30;116(6):1159-1164. doi: 10.1160/TH16-02-0137. Epub 2016 Sep 1.
• Background Blomback M, He S, Bark N, Wallen HN, Elg M. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol. 2011 Mar;152(6):758-65. doi: 10.1111/j.1365-2141.2010.08546.x. Epub 2011 Jan 20.
• Background Stoner MC, Calligaro KD, Chaer RA, Dietzek AM, Farber A, Guzman RJ, Hamdan AD, Landry GJ, Yamaguchi DJ; Society for Vascular Surgery. Reporting standards of the Society for Vascular Surgery for endovascular treatment of chronic lower extremity peripheral artery disease. J Vasc Surg. 2016 Jul;64(1):e1-e21. doi: 10.1016/j.jvs.2016.03.420.
• Background Siablis D, Karnabatidis D, Katsanos K, Kagadis GC, Kraniotis P, Diamantopoulos A, Tsolakis J. Sirolimus-eluting versus bare stents after suboptimal infrapopliteal angioplasty for critical limb ischemia: enduring 1-year angiographic and clinical benefit. J Endovasc Ther. 2007 Apr;14(2):241-50. doi: 10.1177/152660280701400217.
• Background Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
• Background Mills JL Sr, Conte MS, Armstrong DG, Pomposelli FB, Schanzer A, Sidawy AN, Andros G; Society for Vascular Surgery Lower Extremity Guidelines Committee. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014 Jan;59(1):220-34.e1-2. doi: 10.1016/j.jvs.2013.08.003. Epub 2013 Oct 12.
• Background Bollinger A, Breddin K, Hess H, Heystraten FM, Kollath J, Konttila A, Pouliadis G, Marshall M, Mey T, Mietaschk A, Roth FJ, Schoop W. Semiquantitative assessment of lower limb atherosclerosis from routine angiographic images. Atherosclerosis. 1981 Feb-Mar;38(3-4):339-46. doi: 10.1016/0021-9150(81)90050-2.
• Background Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2011;9(8):672-7. doi: 10.1016/j.ijsu.2011.09.004. Epub 2011 Oct 13. No abstract available.
• Background Avezum A, Lopes RD, Schulte PJ, Lanas F, Gersh BJ, Hanna M, Pais P, Erol C, Diaz R, Bahit MC, Bartunek J, De Caterina R, Goto S, Ruzyllo W, Zhu J, Granger CB, Alexander JH. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation. 2015 Aug 25;132(8):624-32. doi: 10.1161/CIRCULATIONAHA.114.014807. Epub 2015 Jun 23.
• Background Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/NEJMoa1302507. Epub 2013 Jul 1.
• Background Biagioni RB, Biagioni LC, Nasser F, Burihan MC, Ingrund JC, Neser A, Miranda F Jr. Infrapopliteal Angioplasty of One or More than One Artery for Critical Limb Ischaemia: A Randomised Clinical Trial. Eur J Vasc Endovasc Surg. 2018 Apr;55(4):518-527. doi: 10.1016/j.ejvs.2017.12.022.
• Biagioni RB, Lopes RD, Agati LB, Sacilotto R, Wolosker N, Sobreira ML, de Freitas Soares BL, Joviliano EE, Bernardi WH, Junior VC, Caffaro RA, Fioranelli A, Van Bellen B, Casella IB, Fidelis RJR, Flumignan RLG, Comerota AJ, Ramacciotti E. Rationale and design for the study Apixaban versus ClopidoGRel on a background of aspirin in patient undergoing InfraPoPliteal angioplasty for critical limb ischemia: AGRIPPA trial. Am Heart J. 2020 Sep;227:100-106. doi: 10.1016/j.ahj.2020.06.010. Epub 2020 Jun 23.

Drugs

Indications