Therapeutic angiogenesis
Therapeutic angiogenesis (administration of vascular growth factors) has emerged as a possible alternative treatment for peripheral arterial disease (PAD). Preliminary evidence suggests that autologous bone marrow mononuclear cells implantation in PAD patients with critical limb ischemia may improve lower limb ischemic symptoms.[90]Paraskevas KI, Mikhailidis DP. Angiogenesis: a promising treatment option for peripheral arterial disease. Curr Vasc Pharmacol. 2008Apr;6(2):78-80.
http://www.ncbi.nlm.nih.gov/pubmed/18393907?tool=bestpractice.com
[91]Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease: meta-analysis and systematic review of the literature. Atherosclerosis. 2010 Mar;209(1):10-7.
http://www.ncbi.nlm.nih.gov/pubmed/19740466?tool=bestpractice.com
This is also supported by the results of two systematic reviews.[92]Moazzami B, Mohammadpour Z, Zabala ZE, et al. Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev. 2022 Jul 8;7:CD008347.
https://www.doi.org/10.1002/14651858.CD008347.pub4
http://www.ncbi.nlm.nih.gov/pubmed/35802393?tool=bestpractice.com
[93]Teraa M, Sprengers RW, van der Graaf Y, et al. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013 Dec;258(6):922-9.
http://www.ncbi.nlm.nih.gov/pubmed/23426345?tool=bestpractice.com
However, further data from larger studies are required before reaching any firm conclusions.
Balloon catheter
The Food and Drug Administration (FDA) approved the Lutonix® 035 drug-coated balloon percutaneous transluminal angioplasty (PTA) catheter, the IN.PACT Admiral® paclitaxel-coated PTA balloon catheter, and the Stellarex® drug-coated angioplasty balloon for the treatment of femoropopliteal lesions.[94]Managed Healthcare Executive. FDA approves first drug-coated angioplasty balloon catheter. Oct 2014 [internet publication].
https://www.formularywatch.com/view/fda-approves-first-drug-coated-balloon-catheter
[95]US Food and Drug Administration. Medtronic IN.PACT Admiral paclitaxel-coated PTA balloon catheter - P140010. Dec 2014 [internet publication].
https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140010c.pdf
[96]Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med. 2015 Jul 9;373(2):145-53.
http://www.nejm.org/doi/full/10.1056/NEJMoa1406235
http://www.ncbi.nlm.nih.gov/pubmed/26106946?tool=bestpractice.com
[97]Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015 Feb 3;131(5):495-502.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323569
http://www.ncbi.nlm.nih.gov/pubmed/25472980?tool=bestpractice.com
These drug-coated balloons may improve long-term angioplasty outcomes. However, one Cochrane review found that current evidence is insufficient to prove this.[98]Kayssi A, Al-Jundi W, Papia G, et al. Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for the treatment of in-stent restenosis of the femoropopliteal arteries. Cochrane Database Syst Rev. 2019 Jan 26;(1):CD012510.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353053
http://www.ncbi.nlm.nih.gov/pubmed/30684445?tool=bestpractice.com
[ 
]
How does drug‐eluting angioplasty compare with uncoated balloon angioplasty for adults with in‐stent restenosis of femoropopliteal arteries?/cca.html?targetUrl=https://www.cochranelibrary.com/cca/doi/10.1002/cca.2834/fullShow me the answer Furthermore, one meta-analysis found a signal for increased mortality in patients treated with paclitaxel-coated balloons and stents.[99]Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018 Dec 18;7(24):e011245.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405619
http://www.ncbi.nlm.nih.gov/pubmed/30561254?tool=bestpractice.com
This has led the FDA to issue a warning advising that patients who have been treated with these devices should be diligently monitored, and that clinical studies should continue.[100]US Food and Drug Administration. UPDATE: treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality. Aug 2019 [internet publication].
Vorapaxar
Vorapaxar is a protease-activated receptor-1 (PAR-1) antagonist that acts as a potent antiplatelet agent. In clinical trials that included patients with recent myocardial infarction or PAD, the addition of vorapaxar on a background of aspirin and/or clopidogrel was associated with a reduction in major adverse cardiovascular events during long-term follow-up. A subgroup analysis of patients with PAD also suggested that vorapaxar was associated with a reduction in acute limb ischemia.[101]Gryka RJ, Buckley LF, Anderson SM. Vorapaxar: the current role and future directions of a novel protease-activated receptor antagonist for risk reduction in atherosclerotic disease. Drugs R D. 2017 Mar;17(1):65-72.
http://www.ncbi.nlm.nih.gov/pubmed/28063023?tool=bestpractice.com
Vorapaxar is approved by the FDA for the reduction of thrombotic cardiovascular events in patients with a history of PAD.
Intravascular lithotripsy
Intravascular lithotripsy is a technique that involves using pressure waves to soften arterial plaque in calcified peripheral arterial disease, which may have benefit in selected patients with calcified arteries.[102]Tepe G, Brodmann M, Werner M, et al. Intravascular lithotripsy for peripheral artery calcification: 30-day outcomes from the randomized Disrupt PAD III trial. JACC Cardiovasc Interv. 2021 Jun 28;14(12):1352-61.
https://www.sciencedirect.com/science/article/pii/S1936879821006853
http://www.ncbi.nlm.nih.gov/pubmed/34167675?tool=bestpractice.com
[103]Tepe G, Brodmann M, Bachinsky W, et al. Intravascular lithotripsy for peripheral artery calcification: mid-term outcomes from the randomized Disrupt PAD III trial. J Soc Cardiovasc Angiogr Interv. 2022 Jul-Aug;1(4):100341.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11307657
http://www.ncbi.nlm.nih.gov/pubmed/39131928?tool=bestpractice.com
Further studies are needed.[104]National Institute for Health and Care Excellence. Intravascular lithotripsy for calcified arteries in peripheral arterial disease. Jan 2024 [internet publication].
https://www.nice.org.uk/guidance/ipg780