A look at the incidence and impact on outcomes.
By John H. Rundback, MD; Peter A. Schneider, MD; and Richard E. Fulton, MD
Chronic limb-threatening ischemia (CLTI) is a steadily rising vascular threat due to globally increasing rates of diabetes mellitus and chronic kidney disease, affecting nearly 1% to 2% of people worldwide and > 10% of patients with peripheral artery disease (PAD) and resulting in 300 to 500 major nontraumatic amputations each day in the United States.1 CLTI often remains undiagnosed until late in its course. One consequence of this is that fewer than half of patients receive an appropriate vascular evaluation prior to undergoing an above-ankle amputation.2 Endovascular therapies continue to evolve for the treatment of popliteal and infrapopliteal occlusive disease, with recent data showing favorable limb salvage rates with coordinated care models, vascular intervention, and diligent surveillance-driven reintervention.3-6 Despite this, there are unique challenges to CLTI procedures that have limited the widespread adoption of these techniques, including complex anatomic patterns of dense calcification and chronic total occlusion (CTO), nonreconstructible vascular beds with impaired or absent pedal circulation, procedure-related arterial dissection, recoil and early restenosis, and distal embolization. Over the past decade, these challenges have spawned the development of many new and investigational technologies to improve outcomes, including the Tack endovascular system (Philips) and other dedicated tibial scaffolds,7-10 arteriovenous flow reversal and deep venous arterialization tools,11 and devices specific to treating calcium.5,12 For distal popliteal and tibiopedal arterial interventions, there remains one dominant procedural and clinical problem that has not been well studied and for which there are no dedicated solutions: procedure-related embolization.
Procedure-related embolization during CLTI interventions is a frequent but not well-assessed problem and encompasses a broad spectrum of possible injury and consequences (Sidebar). In a recent study of distal embolic protection during superficial femoral artery interventions, captured debris of < 1 mm was noted in 98% of cases, 1 to 2 mm in 22% of cases, and > 2 mm in 9% of cases.13 Because the smallest pore size of distal embolic protection filters is 110 µm, embolization of nonaggregated, smaller-sized material may be overlooked. In CLTI, because of the unique characteristics of infrapopliteal CTOs, longer lesions, and calcification, the propensity for embolization is potentially greater than in other vascular beds. Previous data have suggested that these more complex features of occlusions and lesion length are associated with higher rates of distal embolization.14 Embolization has been demonstrated to be an important cause of compromised runoff after vascular procedures, which directly correlates with recurrent symptoms, repeat interventions, and limb loss.15 Importantly, the concept of “clinically relevant” embolization, as defined by clinician or core lab identification of a newly recognized abrupt distal vessel cutoff, is the most obvious example of embolic occlusion but likely represents only a small fraction of the microembolization occurring during procedures that affects the smaller arteries of the foot, pedal arterioles, and capillaries. In fact, for femoropopliteal interventions, angiographic evidence of embolization represents only 5% of emboli identified using microscopic identification of embolic protection filters.16 Consequently, microembolization has not been well studied, in effect acknowledged as an acceptable occurrence in limb salvage procedures. It is striking that despite the tremendous advances in vascular care over the last 25 years, there is an obvious paucity of data regarding the exact definition of embolization, the frequency of worsening perfusion parameters after CLTI treatments, the best modalities for measuring oxygen delivery to dermal and wound tissues, the content of embolic material (eg, plaque, cholesterol, thrombus, cellular), or the best modes of prevention and treatment of this condition. As the incidence and prevalence of diabetes increases and the vast majority of patients presenting with CLTI have diabetes, the pedal microcirculatory occlusive disease present in these patients makes them particularly susceptible to the negative consequences of intraprocedural embolization, even when this phenomenon is not readily apparent.
THE CLINICAL SPECTRUM
DURING CLTI PROCEDURES
• Anatomic cutoff
• No/slow flow
• Perfusion deficits
• Loss of wound blush and worsening transcutaneous oxygen pressure/skin perfusion pressure
• Delayed wound healing
• Repeated procedures (progressive loss of runoff)
• Unplanned amputation
THE MICROEMBOLIZATION PHENOMENON
There is evidence that microscopic material liberated downstream during endovascular procedures is a common event and cause of unfavorable short- and longerterm outcomes (Table 1).6,17-25 Within the spectrum of adverse events of embolization, this is seen in the wide range of clinical implications, including postprocedural pain and blistering (ie, livedo reticularis), additional unplanned thrombectomy or thrombolytic procedures, acute worsening ischemia, repeat interventions (and their associated radiation exposure, contrast load, and cost), and microcirculatory injury. The latter is particularly alarming and can be a substantial cause of described complications, including slow or no reflow, compromised perfusion, delayed or absent wound healing, unplanned amputation, and limb loss (Figure 1). Improved anklebrachial indices after revascularization do not correlate with improvements in microcirculation as measured by transcutaneous oxygen tension measurements, reflecting differences in assessing procedural outcomes in large versus small arteries of the foot.26 The observed phenomenon of delayed increase in measurable perfusion,26 as well as cases in which there is no hemodynamic improvement after treatment, may often be due to embolization, with data suggesting that patients without immediate clinical improvement do poorly in terms of limb salvage.12 Finally, in a study of 161 patients with CLTI undergoing tibiopedal angioplasty, a “slow-flow” angiographic pattern was seen in 18.6%, was more common in the presence of severe calcification and CTO, and was associated with lower wound healing rates (1-year wound healing, 57% vs 77%) and major amputation (1-year amputation-free rate, 60% vs 88%) compared to patients with an absence of slow flow.27 Slow flow is also associated with lower postintervention skin perfusion pressures.20 Unplanned rehospitalization occurs in > 15% of patients with PAD and CLTI, predominantly due to pedal sepsis or wound worsening. Almost one-quarter of these readmitted patients undergo an additional revascularization procedure (8.2%) or major amputation (11.7%).28 In a study of 8,726 patients from the Eastern Vascular Society, 421 (4.8%) of CLTI patients underwent unplanned amputation within 30 days of an index procedure.29 An analysis of 13,258 patients undergoing tibiopedal interventions using Medicare data reported progressive gangrene as the most common limb-based cause for hospital readmission (37%), with 44% undergoing minor or major amputation.30 In the EUCLID study, which compared monotherapy with ticagrelor or clopidogrel, the risk of limb deterioration was fourfold higher in patients with prior revascularization.31 Perfusion imaging (including indocyanine green imaging [IGI], transcutaneous oxygen tension measurements, and skin perfusion pressure) provides a unique method to assess otherwise potentially unrecognized procedural microemboli and is a valuable surrogate due to the recognized correlation between these parameters and limb outcomes.32-34 This is supported by recent evidence that microvascular disturbance is associated with major amputation.35 In a study of patients (104 limbs) undergoing open or endovascular revascularization, 8.8% of patients had worse IGI parameters despite technically successful revascularization.24 Mironov et al found decreased ingress rates into the foot on IGI in 39% of patients treated with angioplasty and stenting, with more than one-half in the infrapopliteal distribution.25 Of note, Colvard et al noted that embolic events detected using laser-assisted fluorescence imaging may not be visible by conventional angiography.36 In a smaller evaluation of 14 patients undergoing continuous near-infrared spectroscopy measurements of foot oxygenation during endovascular treatment for CLTI, five (35%) patients showed acute deterioration at procedure completion, although parameters did improve on 4-week evaluation.37 Although clinical outcomes were not reported, these findings suggest acute embolic injury during these procedures
Figure 1. Patterns of embolization. Macroembolization occurring with posterior tibial artery stenosis (arrows) (A) treated with angioplasty alone (B, C). Baseline pedal angiography (D) compared with postprocedural abrupt embolic arterial cutoff of the common plantar artery (open arrow) (E). Microembolization occurring with anterior tibial artery CTO (brackets) (F) treated with atherectomy and angioplasty (G, H). Baseline (I) compared with marked reduction in visualized digital arteries at completion (J).
PARTICULATE EMBOLIZATION FROM DRUG-COATED DEVICES
The increased clinical utility of drug-coated and drugeluting devices has transformed interventional medicine but may provide a unique hazard for below-the-knee interventions. The occurrence of polymer-related embolization has been well described as an “elusive” and possibly pernicious event.38 For patients who underwent intervention with drug-coated balloons (DCBs) (and possibly drug-eluting stents), particulate embolization of polymer or paclitaxel into wound beds creates a dual pathway of damage due to physical obstruction plus antiproliferative effects in vulnerable tissues, resulting in delayed healing and potentially a higher risk of amputation. In a swine study, Granada et al found dose-related paclitaxel particulate embolization in limb wound beds, although healing and epithelialization in these healthy subjects were not inhibited.39 In contrast, in the IN.PACT DEEP trial, higher rates of amputation were observed with the use of DCBs compared with traditional balloons.40 Clearly, more investigation of microcirculatory effects is needed to better understand the potential downstream tissue effects of both antiproliferative-coated devices as well as their polymer excipients.
Despite improvements in revascularization for CLTI over the past decade, clinical success may be limited by unrecognized procedural embolization. The assessment of treatment endpoints has historically focused on angiographic findings, with an inherent underappreciation of microcirculatory damage. Because most CLTI patients have preexisting microcirculatory compromise, they are especially vulnerable to procedure-related embolization, which may limit clinical improvement or promote further clinical deterioration despite successful revascularization. Further efforts to quantify and find solutions to this limitation of limb salvage procedures can potentially improve outcomes for these patients.
1. Farber A. Chronic limb-threatening ischemia. N Engl J Med. 2018;379:171-180. doi: 10.1056/NEJMcp1709326
2. Goodney PP, Travis LL, Nallamothu BK, et al. Variation in the use of lower extremity vascular procedures for
critical limb ischemia. Circ Cardiovasc Qual Outcomes. 2012;5:94-102. doi: 10.1161/CIRCOUTCOMES.111.962233
3. Scatena A, Petruzzi P, Ferrari M, et al. Outcomes of three years of teamwork on critical limb ischemia in patients
with diabetes and foot lesions. Int J Low Extrem Wounds. 2012;11:113-119. doi: 10.1177/1534734612448384
4. Nakano M, Hirano K, Iida O, et al. Prognosis of critical limb ischemia in hemodialysis patients after isolated
infrapopliteal balloon angioplasty: results from the Japan below-the-knee arterial treatment (J-BEAT) registry.
J Endovasc Ther. 2013;20:113-124. doi: 10.1583/11-3782.1
5. Iida O, Nakamura M, Yamauchi Y, et al. 3-year outcomes of the OLIVE Registry, a prospective multicenter study
of patients with critical limb ischemia: a prospective, multi-center, three-year follow-up study on endovascular
treatment for infra-inguinal vessel in patients with critical limb ischemia. JACC Cardiovasc Interv. 2015;8:1493-
1502. doi: 10.1016/j.jcin.2015.07.005
6. Giannopoulos S, Secemsky EA, Mustapha JA, et al. Three-year outcomes of orbital atherectomy for the
endovascular treatment of infrainguinal claudication or chronic limb-threatening ischemia. J Endovasc Ther.
2020;27:714-725. doi: 10.1177/1526602820935611
7. Geraghty PJ, Adams GL, Schmidt A, et al. Twelve-month results of Tack-optimized balloon angioplasty using
the Tack endovascular system in below-the-knee arteries (TOBA II BTK). J Endovasc Ther. 2020;27:626-636.
8. LIFE-BTK randomized controlled trial. Clinicaltrials.gov website. Accessed March 17, 2022. https://clinicaltrials.
9. A clinical evaluation of the MicroStent® peripheral vascular stent in subjects with arterial disease below the knee
(STAND). Clinicaltrials.gov website. Accessed March 17, 2022. https://clinicaltrials.gov/ct2/show/NCT03477604
10. The DES BTK vascular stent system vs PTA in subjects with critical limb ischemia (SAVAL). Clinicaltrials.gov
website. Accessed March 17, 2022. https://clinicaltrials.gov/ct2/show/NCT03551496
11. Clair DG, Mustapha JA, Shishehbor MH, et al. PROMISE I: early feasibility study of the LimFlow system for
percutaneous deep vein arterialization n no-option chronic limb-threatening ischemia: 12-month results. J Vasc
Surg. 2021;74:1626-1635. doi: 10.1016/j.jvs.2021.04.057
12. Ichihashi S, Takahara M, Fujimura N, et al. Changes in skin perfusion pressure after endovascular treatment for
chronic limb-threatening ischemia. J Endovasc Ther. 2021;28:208-214. doi: 10.1177/1526602820963932
13. Shammas NW, Pucillo A, Jenkins JS, et al. Wirion embolic protection system in lower extremity arterial
interventions: results of the pivotal WISE LE trial. JACC Cardiovasc Interv. 2018;11:1995-2003. doi: 10.1016/j.
14. Boc A, Blinc A, Boc V. Distal embolization during percutaneous revascularization of the lower extremity arteries.
Vasa. 2020;49:389-394. doi: 10.1024/0301-1526/a000877
15. Davies MG, Saad WE, Peden EK, et al. Impact of runoff on superficial femoral artery endoluminal interventions
for rest pain and tissue loss. J Vasc Surg. 2008;48:619-626. doi: 10.1016/j.jvs.2008.04.013
16. Ochoa Chaar CI, Shebl F, Sumpio B, et al. Distal embolization during lower extremity endovascular interventions. J Vasc Surg. 2017;66:143-150. doi: 10.1016/j.jvs.2017.01.032
17. Shammas NW, Shammas G, Dippel E, Jerin M. Intraprocedural outcomes following distal lower extremity
embolization in patients undergoing peripheral percutaneous interventions. Vasc Dis Mgmt. 2009;6:58-61.
18. Ward TJ, Piechowiak RL, Patel RH, et al. Revascularization for critical limb ischemia using the SpiderFX embolic
protection device in the below-the-knee circulation: initial results. J Vasc Interv Radiol. 2014;25:1533-1538.
19. Mustapha JA, Diaz-Sandoval LJ, Adams G, et al. Lack of association between limb hemodynamics and response
to infrapopliteal endovascular therapy in patients with critical limb ischemia. J Invasive Cardiol. 2017;29:175-180.
20. Tokuda T, Kirano K, Sakamoto Y, et al. Incidence and clinical outcomes of the slow-flow phenomenon after
infrapopliteal balloon angioplasty. J Vasc Surg. 2017;65:1047-1054. doi: 10.1016/j.jvs.2016.08.118
21. Lee MS, Mustapha J, Beasley R, et al. Impact of lesion location on procedural and acute angiographic outcomes
in patients with critical limb ischemia treated for peripheral artery disease with orbital atherectomy: a CONFIRM
registries subanalysis. Cathet Cardiovasc Interv. 2016;15:440-445. doi: 10.1002/ccd.26349
22. Rymer JA, Kennedy KF, Lowenstern AM, et al. In-hospital outcomes and discharge medication use among
patients with critical limb ischemia versus claudication. J Am Coll Cardiol. 2020;75:704-706. doi: 10.1016/j.
23. Mukherjee D, Liu C, Jadali A, et al. Effects of peripheral arterial disease interventions on survival: a propensityscore matched analysis using VQI data. Ann Vasc Surg. 2022;79:162-173. doi: 10.1016/j.avsg.2021.08.004
24. Settembre N, Kauhanen P, Alback A, et al. Quality control of the foot revascularization using indocyanine green
fluorescence imaging. World J Surg. 2017;41:1919-1926. doi: 10.1007/s00268-017-3950-6
25. Mironov O, Zener R, Eisenberg N, et al. Real-time quantitative measurements of foot perfusion in patients with
critical limb ischemia. Vasc Endovasc Surg. 2019;53:310-315. doi: 10.1177/1538574419833223
26. Pardo M, Alcaraz M, Breijo RF, et al. Increased transcutaneous oxygen pressure is an indicator of revascularization after peripheral transluminal angioplasty. Acta Radiol. 2010;9:990-993. doi: 10.3109/02841851.2010.504968
27. Utsunomiya M, Nakamura M, Nagashima Y, Sugi K. Predictive value of skin perfusion pressure after endovascular therapy for wound healing in critical limb ischemia. J Endovasc Ther. 2014:21:662-670. doi: 10.1583/14-
28. Bodewes TC, Soden PA, Ultee KH, et al. Risk factors for 30-day unplanned readmission following infrainguinal
endovascular interventions. J Vasc Surg. 2017;65:484-494. doi: 10.1016/j.jvs.2016.08.093
29. Yank CK, Goss S, Alcantara S, et al. Risk factors for unplanned amputations within 30 days of infrainguinal
revascularization. J Vasc Surg. 2015;62:813. doi: 10.1016/j.jvs.2015.06.117
30. Vogel TR, Dombrovskiy VY, Carson JL, Graham AM. In-hospital and 30-day outcomes after tibioperoneal interventions in the US Medicare population with critical limb ischemia. J Vasc Surg. 2011;54:109-115. doi: 10.1016/j.
31. Jones WS, Baumgartner I, Hiatt WR, et al. Ticagrelor compared with clopidogrel in patients with prior lower
extremity revascularization for peripheral artery disease. Circulation. 2017;135:241-250. doi: 10.1161/CIRCULATIONAHA.116.025880
32. Kawarada O, Yokoi Y, Higashimori A, et al. Assessment of macro- and microcirculation in contemporary critical
limb ischemia. Cathet Cardiovasc Interv. 2011;78:1051-1058. doi: 10.1002/ccd.23086
33. Misra S, Shishehbor MH, Takahashi EA, et al. Perfusion assessment in critical limb ischemia: principles for understanding and the development of evidence and evaluation of devices: a scientific statement from the American
Heart Association. Circulation. 2019;140:e657-e672. doi: 10.1161/CIR.0000000000000708
34. Castronuovo JJ Jr, Adera HM, Smiell JM, Price RM. Skin perfusion pressure is valuable in the diagnosis of critical
limb ischemia. J Vasc Surg. 1997;26:629-637. doi: 10.1016/s0741-5214(97)70062-4
35. Beckman JA, Duncan MS, Damrauer SM, et al. Microvascular disease, peripheral artery disease, and amputation. Circulation. 2019;140:449-458. doi: 10.1161/CIRCULATIONAHA.119.040672
36. Colvard B, Itoga NK, Hitchner E, et al. SPY technology as an adjunctive measure for lower extremity perfusion.
J Vasc Surg. 2016;64:195-201. doi: 10.1016/j.jvs.2016.01.039
37. Boezeman RPE, Becx BP, van den Heuvel DAF, et al. Monitoring of foot oxygenation with near-infrared
spectroscopy in patient with critical limb ischemia undergoing percutaneous transluminal angioplasty: a pilot
study. Eur J Vasc Endovasc Surg. 2016;52:650-656. doi: 10.1016/j.ejvs.2016.07.020
38. Chopra AM, Mehta M, Bismuth J, et al. Polymer coating embolism from intravascular medical devices –
a clinical literature review. Cardiovasc Pathol. 2017;30:45-54. doi: 10.1016/j.carpath.2017.06.004
39. Granada JF, Ferrone M, Melnick G, et al. Downstream paclitaxel released following drug-coated balloon
inflation and distal limb wound healing in swine. JACC Basic Transl Sci. 2021;6:416-427. doi: 10.1016/j.
40. Zeller T, Micari A, Scheinert D, et al. The IN.PACT DEEP clinical drug-coated balloon trial: 5-year outcomes. JACC
Cardiovasc Interv. 2020;13:431-443. doi: 10.1016/j.jcin.2019.10.059