2014 Volume 78 Issue 7 Pages 1540-1549
Infrapopliteal arterial disease is a significant cause of critical limb ischemia (CLI), whether single-segment or multisegment disease. The collaboration between the tremendous advancements in endovascular technology and the refinement of endovascular techniques has renewed the classic infrapopliteal interventions during the past decade. With this paradigm shift in the treatment of CLI, the role of a comprehensive approach of different disciplines for tissue loss is becoming greater. Given the increasing global burden of CLI, we review the cutting-edge diagnostic and endovascular approaches to infrapopliteal artery disease, and the importance of wound management in optimizing clinical outcomes. (Circ J 2014; 78: 1540–1549)
There is an increasing global burden of peripheral artery disease linked with diabetes mellitus and chronic kidney disease.1–3 With these pandemic conditions, critical limb ischemia (CLI), the most advanced stage of peripheral artery disease, is an emerging public health issue. Recently, the prevalence and incidence of CLI were reported to be 0.23% and 0.20%, respectively, in those over the age of 65.4 A hallmark of contemporary CLI is the broad spectrum of clinical manifestations such as resting pain, ulcer or gangrene complicated by ischemia, neuropathy and infection. Thus, dissemination of a comprehensive approach of different disciplines for CLI is an urgent requisite.
As infrapopliteal artery disease is the mainstay of CLI, whether in single or multiple segments,5–7 bypass surgery has been a traditional treatment option, especially for patients without severe comorbidities who can tolerate general anesthesia and an invasive procedure. However, the collaboration between advanced technology and technical refinement has led to sophisticated classic infrapopliteal interventions.8–16 More recently, even below-the-ankle interventions have been advocated for the treatment of symptomatic pedal artery disease.17–22 Updated guidelines have asserted an expanding role of endovascular therapy for the treatment of CLI in patients on the verge of major amputation and at high risk for cardiovascular events and death.23,24 According to the ACC/AHA guideline, the endovascular option is primarily recommended for patients with an estimated limited life expectancy within 2 years. Furthermore, according to the ESC guideline, emphasis is placed on an “endovascular-first” strategy if technically feasible. In cases of failed bypass, endovascular back-up also could be a last resort. With this paradigm shift in the treatment of CLI, the significance of wound issues has increased. This review describes the cutting-edge diagnostic and endovascular therapeutic approaches to infrapopliteal artery disease, and the extensive role of proactive wound management in order to optimize clinical outcomes.
Despite the expanded armamentarium of less invasive diagnostic techniques, catheter-based infrapopliteal angiography using digital subtraction angiography technology remains the gold standard for accurate diagnosis and planning of endovascular procedures, which are mostly ad hoc interventions. As complex lesions in association with myriad collateral circulation are predominant in infrapopliteal artery disease, appreciation of the anatomy based on angiography is requisite for improving interventional outcomes. In patients with renal failure, carbon dioxide infrapopliteal angiography might be considered in order to prevent contrast nephropathy.25
Infrapopliteal angiography requires an optimal projection for each segment. The contralateral anterior oblique view is indispensable for appreciation of the positional relationship between the distal popliteal artery, the proximal anterior tibial artery and the tibioperoneal trunk, whereas the ipsilateral anterior oblique view is ideal for differentiation of the tibioperoneal trunk, the proximal posterior tibial artery and the peroneal artery. Also, contralateral anterior oblique and ipsilateral cranial views can provide a better understanding of the distal crural artery and the pedal arch conditions. Standard anatomy is shown in Figures 1A,B. In cases of occlusive lesions in both or either of the anterior tibial artery or posterior tibial artery, which is a typical pattern of severe infrapopliteal artery disease, the peroneal artery can serve as a collateral source (Figure 1C). In cases of pedal artery disease, the foot artery branches such as the medial and lateral malleolar arteries, the medial and lateral tarsal arteries, and the arcuate artery can be developed as collateral sources (Figure 1D). The foot artery branches and digital arteries might not be angiographically visible because of occlusive lesions, occult vessels or their absence.
Standard infrapopliteal anatomy in the left leg on digital subtraction angiography (anteroposterior view). (A) Proximal, (B) distal. (C) Typical angiographic appearance in infrapopliteal artery disease. Note the distal segments of anterior tibial artery (→) and posterior tibial artery (▶) are supplied through the collateral vessels from the peroneal artery (➡). (D) Development of collateral circulation in pedal artery disease. In this case, the medial tarsal artery develops to the lateral planter artery and the deep plantar arch as a collateral source because of the diseased dorsalis pedis artery. (E) Representative case of underlying infrapopliteal variant (cited from reference 26). Diagnostic angiography of the right leg shows multiple severe stenoses in the proximal peroneal artery and the paramalleolar posterior tibial artery (→). Note that chronic total occlusion with poor collateral vessels (➡) in the distal peroneal artery angiographically appears to connect with the dorsalis pedis artery (▶). The anterior tibial artery is considered to be hypoplastic. (F) Lateral plantar artery supplying blood flow to the toes in the case of occlusion of the dorsalis pedis artery. Although the dorsalis pedis artery is occluded, the prominent lateral plantar artery (large arrow) is the main supply to the toes through the metatarsal arteries originating from the deep planar arch (small arrow). (G) The dorsalis pedis artery supplying blood to the toes in the case of occlusion of the lateral plantar artery. Note that the dorsalis pedis artery (large arrow) alternatively supplies blood flow to the toes through the metatarsal arteries from the deep plantar arch (small arrow).
Variants in the popliteal artery branching pattern consisting of aplasty or hypoplasty of the tibial artery, high take-off of the tibioperoneal arteries, trifurcation and an anterior tibioperoneal trunk are not uncommon.26 Given that approximately 10% of the population has these variants, differentiation of occlusion and variation represents a challenging task in cases of severe infrapopliteal artery disease. When an infrapopliteal variant is observed in 1 extremity, there is a 28–50% probability of the same pattern on the other side. With the features of infrapopliteal variant vessels in mind, insight into the possibility of underlying variations is the key to successful identification of infrapopliteal variants (Figure 1E).
Furthermore, the greater variation in the foot arteries, especially on the dorsum, can be confusing because the standard pattern of distribution of the branches of the dorsalis pedis artery is not common.27 Each toe can be supplied via metatarsal arteries from the dorsal or plantar system depending on the dominance of supply and the extent of occlusive lesions (Figures 1F,G). Similarly, the hallux can be supplied by the medial plantar artery, the plantar metatarsal artery from the lateral plantar artery and the dorsal metatarsal artery from the dorsalis pedis artery, depending on the dominance of supply and the extent of occlusive lesions.
Clinically, rest pain and tissue loss (ulcers and gangrene) are definite indications for infrapopliteal intervention. In patients with multisegment disease, the general rule is to increase upstream flow to the greatest extent possible by first treating significant suprapopliteal lesions. The time interval between suprapopliteal and infrapopliteal interventions can vary according to clinical manifestations, the status of ischemia, and the operator’s skill level. Hemodynamically, the ankle-brachial index (ABI) or ankle pressure, traditional markers of the macrocirculation, can be falsely high because of excessive calcification in the tibial artery.28 Also, these markers do not reflect blood flow below the ankle. Thus, with the limited utility of macrocirculation assessment, enthusiastic evaluation of the microcirculation is necessary in the setting of CLI.5,29–31 Microcirculation assessment with skin perfusion pressure (SPP) or transcutaneous oxygen pressure (TCPO2) is strongly recommended, especially for CLI patients undergoing infrapopliteal interventions.32,33 In particular, SPP has been gaining popularity because of its simplicity, reproducibility, and reliability. According to Castronuovo et al,31 SPP values of 40 mmHg or higher are associated with a high likelihood of wound healing in critically ischemic limbs (Figure 2A). Thus, a SPP value less than 40 mmHg reflect a strong indication for revascularization (including reintervention) whereas SPP between 40 and 50 mmHg represents an intermediate range.
(A) Relationship between skin perfusion pressure (SPP) and probability of wound healing (revised based on reference 31). SPP ≥40 mmHg is associated with a high likelihood of wound healing. (B) Establishment of at least 1 straight-line flow to the foot as the primary endovascular strategy. Pre: baseline angiography showing severe infrapopliteal artery disease in the left leg. Post: final angiography after successful revascularization of the long total occlusion in the anterior tibial artery, showing an excellent result with the establishment of straight-line flow to the foot (citation from reference 12). (C) Clinically-driven below-the-ankle intervention. Pre: baseline angiography showing total occlusion of the dorsalis pedis artery as well as severe stenosis in the lateral plantar artery (arrow). Pedal angioplasty: balloon angioplasty of the pedal arch following the guidewire crossing from the lateral plantar artery to the dorsalis pedis artery through the deep plantar artery. Post: final angiography showing revival of the pedal arch.
The primary goal of infrapopliteal intervention should be establishing at least 1 straight-line flow to the foot in each limb (Figure 2B). With the development of guidewire technology and proliferative endovascular chronic total occlusion (CTO) crossing techniques, current procedural success rates could be approximately 90%.14,15 Given that the severity of pedal arch is significantly associated with wound healing,15,34,35 below-the-ankle intervention based on an assessment of the microcirculation such as SPP or TCPO2 is a key component of treating challenging cases, together with liberal debridement12,18,32 (Figure 2C). If technically feasible, complete revascularization (3-vessel revascularization) may enhance wound healing. In addition to close clinical follow-up of the wound, a couple of reinterventions might be inevitable.15,36 Serial evaluation of SPP (eg, the day after the procedure, 7 days later, 1 month later) until complete wound healing can facilitate timely reintervention. Infrapopliteal intervention can also serve as a bridge therapy to bypass surgery after the achievement of infection control. In cases of the need for frequent repeat intervention during a short time, shifting treatment toward the surgical option can be considered if the patients can tolerate general anesthesia and bypass surgery with good risk.
In our practice, dual antiplatelet therapy is given at least 2 days before the procedure and continued until 30 days after the procedure. Also, a relatively low-dose (3,500–5,000 IU) of heparin appears to be acceptable for Japanese patients undergoing current lower limb interventions.12,15 However, there is no consensus regarding the established protocol of antiplatelet therapy and heparinization.
Stenotic lesions can be crossed in the same fashion as in a coronary intervention. With the advent of dedicated guidewires, a variety of crossing techniques have emerged in the field of infrapopliteal intervention (Figure 3).14 In the clinical setting, combining these techniques may increase the success rate of crossing, and intraluminal or subintimal tracking can occur in either direction and with each type of technique. Thus, different scenarios can be observed during the passing of CTO lesions (true-to-true, true-to-false-to-true, etc). In a challenging calcified CTO, a loop technique potentially carries the risk of breakage of the guidewire or inability to remove the curled tip of guidewire. Besides vascular access complications and contrast-induced nephropathy, knowledge of the complications of infrapopliteal intervention is indispensable for interventional cardiologists.
Steps in the crossing techniques for chronic total occusion of the infrapopliteal (cited from reference 14). Antegrade approach using a variety of techniques (stand alone or combination) can be primarily considered. Just in cases of failed antegrade crossing, a retrograde approach can be considered. CART, controlled antegrade and retrograd tracking and dissection.
Vessel spasm can occur in less calcified vessels and may compromise flow when delivering equipment or performing procedures. If spasm results in diminished flow, intra-arterial nitroglycerin or removal of the device works well. Clinically or angiographically relevant distal embolization is rare, but can be significant in patients with a poor vascular bed. If large filling defects consistent with embolization become apparent, direct aspiration with manual or balloon angioplasty can be of great help. Flow-limiting dissection should be treated with either prolonged balloon inflation or implantation of a stent. Crural artery perforation or vessel rupture seems to rarely result in compartment syndrome. Guidewire-induced vessel perforation can almost always be managed straightforwardly, and prolonged balloon inflation might be able to seal the bleeding site. External compression of the vessel and/or compression of the ipsilateral common femoral artery and/or popliteal artery could be potentially of help to manage bleeding.
Balloon angioplasty is notorious for its high rates of restenosis (50–70%) and reintervention (approximately 50%) within 6–12 months, but it can achieve acceptable limb salvage rates15,37 (Figure 4). Bare metal stents (BMS), whether balloon-expandable or self-expandable, have also failed to significantly improve restenosis rates (≈50%), although the use of a scaffolding device for an acute result is attractive (Figure 4).38,39 Thus, liberal use of reintervention has made infrapopliteal intervention a viable option.
Currently, there are 3 major approaches to maintaining infrapopliteal vessel patency. First is the use of a drug-eluting balloon (DEB) designed to release paclitaxel into the media of the angioplasty site to reduce the restenosis from neointimal hyperplasia by suppressing smooth muscle proliferation. A wide range of DEBs is available to accommodate the unique anatomy of the calf and foot in terms of vessel size and length. The benefits of DEBs are definitely attractive: comparably low cost, avoidance of local inflammation caused by drugs or polymers for months or years, freedom from permanent stent fracture events, no residual metal struts, and accessibility for reintervention compared with stent implantation. Recent studies with mean lesion lengths >100 mm reported restenosis rates <30% compared with 70% for balloon angioplasty (Figure 4).40,41 In the DEBATE BTK trial (a randomized, open label, single-center study comparing DEB and balloon angioplasty), binary restenosis, assessed by angiography in >90% of patients, occurred in 20/74 (27%) lesions in the DEB group vs. 55/74 (74%) lesions in the balloon angioplasty group (P<0.001).41 From the procedural standpoint, there are still some flaws that might cause subsequent acute or late lumen loss by vessel dissection, vessel elastic recoil, or aneurysmal formation. Furthermore, several randomized controlled trials of DEBs vs. standard balloons are currently ongoing to demonstrate the considerable potential of DEBs. Also, the potential risk of vasculitis because of distal embolization of the active drug and excipient coating is a major concern with this new technology.42
Second, the drug-eluting stent (DES) technology that has revolutionized coronary intervention has been adopted to treat infrapopliteal lesions. As in the coronary setting, the superiority of DES over BMS or standard angioplasty has been proven for infrapopliteal lesions. Recent randomized controlled trials with mean lesion length <50 mm reported approximately 20% restenosis rate for DES at 12 months while BMS showed approximately 50% (Figure 4).43–45 Furthermore, the YUKON BTK study reported a clinical benefit of DES that was a significantly lower amputation rate compared with BMS (5.3% vs. 22.6%, P=0.04).46 However, most DES currently used in the lower leg were designed for the coronary arteries. Infrapopliteal arteries, especially the distal segments, are susceptible to multiple types of mechanical stress such as flexion, torsion, expansion and contraction because of ankle joint movement and compression by surrounding inflexible tendons, tough ligaments and solid bones. This unique situation can increase the potential risk of stent deformities such as stent compression and stent fracture, especially in the distal calf and foot.12,47 Thus, the development of DES platforms designed specifically for the infrapopliteal arteries are necessary.
Thirdly, the bioresorbable vascular scaffold (BVS) is an emerging technology to overcome stent-related issues. ABSORB BTK is a prospective, single-arm, multicenter trial designed to evaluate the safety and efficacy of the AbsorbTM BVS.48 The device has been implanted in up to 90 CLI patients with symptomatic infrapopliteal artery disease in up to 10 clinical trial sites. The primary endpoint is a composite of freedom from major adverse limb events (MALE; major amputation or major reinterventions) within 1 year, or death within 30 days of the procedure. This technology might present a novel option in the treatment of infrapopliteal artery disease.
These promising data regarding restenosis rates and vessel patency allow us to expect a significant reduction in clinically-driven reintervention. Thus, the clinical performance of emerging endovascular technology needs to be addressed in terms of wound healing, limb salvage and the cost-benefit trade-off for the use of the technology.
Measurement of the microcirculation is a reasonable, objective endpoint to assess the effects of revascularization. Clinically, MALE, consisting of reintervention and major amputation, is a proposed objective endpoint in CLI studies. However, in the clinical setting, reintervention is quite straightforward, and the clinical significance of the need for reintervention is different from that of major amputation for CLI patients.
On the other hand, single endpoints such as the amputation-free survival rate, limb salvage rate, and freedom from reintervention rate can offer a better understanding of the clinical landscape after successful infrapopliteal intervention. In a recently published practical study in which stenting was required in 43% of patients during the entire clinical course, amputation-free survival rates were 85.7%, 68.0%, 54.5%, and 39.8% at 6 months, 1, 2, and 5 years, respectively, while limb salvage rates were 96.0%, 92.4%, 86.3%, and 86.3% at the same time points. Moreover, the freedom from reintervention rate was 55.0%, 49.6%, 44.4%, and 36.1% (Figure 5A).15 These finding suggest a substantial discrepancy between freedom from reintervention and avoidance of limb loss, and that the sustained limb salvage rate is related to poor survival and the effects of the competing mortality hazard.
(A) Long-term outcome of infrapopliteal intervention in real-world practice (cited from reference 15). Note that the limb salvage rate can be sustained because of poor survival and liberal reintervention. (B) Comparison of wound healing and limb salvage rates at 12 months after infrapopliteal intervention. (C) Classification of the pedal arch (cited from reference 15). Type 1 : dorsalis pedis and plantar arteries are both patent. Type 2A : only the dorsalis pedis artery is patent. Type 2B : only the plantar artery is patent. Type 3 : dorsalis pedis and plantar arteries are both occluded. (D) Stratified wound healing after infrapopliteal intervention (cited from reference 15). Note that clinical factors such as diabetes and infectious wound are more significantly associated with wound healing than angiographic factors such as the severity of pedal arch disease (pedal arch classification).
In the clinical setting, “complete wound healing” after endovascular therapy can also be an important endpoint for CLI patients with tissue loss because incomplete wound healing is not necessarily an indication for major amputation. It is worthwhile to note that the wound healing rate ranges between 50% and 90% wherever limb salvage rate is approximately 80–90% (Figure 5B).15,33,39,40 As for wound healing time, the mean time to complete wound healing is 4.8 months, with healing rates of 14.2%, 36.8%, 57.5%, 67.9%, and 73.6% at 1, 3, 6, 9, and 12 months, respectively. In particular, diabetic foot and infectious wound as well as pedal arch disease are independently associated with clinical outcomes even after a successful infrapopliteal intervention (Figures 5C,D).15
In Japan, there is almost unlimited availability of medical care for hemodialysis (HD) patients. However, few data are available regarding the outcomes of infrapopliteal intervention for CLI patients on HD. Technical success rates might be lower for HD than for non-HD patients, and HD patients may have several times the risk of wound non-healing, the need for reintervention, and death or major amputation (amputation-free survival) than patients who do not have endstage renal disease.15,49,50
A qualified specialty that organizes multidisciplinary care for wounds should be established in each vascular center.51 Even though tissue loss is complicated by diabetes mellitus and infection, an individualized approach with specialized physicians (plastic surgeon, dermatologist or orthopedic surgeon etc) and nurses can enhance the possibility of clinical success (Figures 6A,B).
(A) Clinical scenario of wound healing supported by reintervention in a 58-year-old man with extensive infectious tissue loss (Rutherford category 6, Wagner grade 6). Immediately after the first debridement of infectious tissue to prevent sepsis, the first infrapopliteal intervention was performed. During the process of wound healing, clinically-driven reintervention was required twice on the basis of skin perfusion pressure (SPP) guidance, and a total of 3 debridements or minor amputations was also performed. Finally, complete wound healing and gait acquisition were achieved. Note the process of wound healing (bleeding and inflammation, granulation, epithelialization and reconstitution) supported by timely intervention. (B) Wound healing by comprehensive approach in a 65-year-old man with endstage renal disease because of diabetic nephropathy referred to the vascular unit for treatment of infectious gangrene on the right 3rd toe. The SPP was 39/22 mmHg (dorsum/plantar side). Wound culture identified MRSA and blood examination demonstrated severe inflammation. Baseline angiography showed severe stenosis in the anterior tibial artery (ATA) and long total occlusion in the posterior tibial artery-plantar artery. The ATA was dilated with balloon angioplasty and successfully recanalized. Despite residual severe pedal arch disease, the SPP increased to 52/27 mmHg, and liberal debridement facilitated complete wound healing in conjunction with administration of appropriate antibiotic agent.This case suggests the importance of treatment strategy based on the assessment of microcirculation.
Diabetes mellitus can change the nature of infrapopliteal occlusive disease. Vessel calcification, endothelial dysfunction, subsequent thrombosis formation, and vasoconstriction can disturb both the macrocirculation and microcirculation.52,53 Foot ischemia can be further impaired by neuropathy; arteriovenous shunting because of autonomic neuropathy, exogenous factors such as excessive loading because of motor and sensory neuropathy and diabetic foot deformity can cause neuroischemic ulcer or gangrene.54 Also, hyperglycemia and impaired immunological responses can dispose purely ischemic wounds to becoming infected ischemic wounds, and subsequent infectious arteritis in the small arteries of the foot can exacerbate ischemia. Consequently, polymicrobial foot infections can range from minimal superficial infection to deep infection including osteomyelitis, and serve as a physical barrier to re-epithelialization and amplify the risk of sepsis. However, liberal removal of the devitalized tissue, empirical or sensitivity-based antibiotic treatment, and epithelialization-stimulating dressings have been proven to improve wound healing and limb salvage rates.55 In cases of severe infection, the priority of treatment is temporary debridement/minor amputation before revascularization in order to prevent the development of sepsis. In cases of uncontrolled infectious tissue loss, major amputation or terminal care can be considered for patients who are not eligible for any revascularization.
The original concept of the angiosome, introduced by Taylor and Palmer in 1987 in the context of flaps for skin healing, is a “3-dimensional (3D)” composite of skin, soft tissue, and bone supplied by a single source artery and its branches.56 Although even the original concept of a 3D angiosome might be less relevant to the in vivo blood supply than to flap design,57 the recent concept of a “2-dimensional (2D)” angiosome as a uniform map of vascular territories with clear boundaries emerged in the field of surgical and endovascular treatment for CLI 5 years ago.58–61 Despite the lack of randomized comparative studies, emphasis was placed on direct revascularization of the artery feeding the 2D angiosome where ischemic ulcers or gangrene exists rather than indirect revascularization. In the middle of the current angiosome boom, more recent studies have raised objections to this approach that sound good in theory.15,34,62–64 These differences in the benefits of the 2D angiosome theory in published studies could be related to the multifactorial nature of CLI. Of great interest, the most recent study using SPP found no significant difference in microcirculation between direct and indirect revascularization, and that approximately half of the feet revascularized had a change in microcirculation that was not consistent with the 2D angiosome theory.65 As each critically ischemic limb has an individual 3D angiosome makeup (Figure 7), even the 3D angiosome theory might be an adjunctive concept to providing an excuse for insufficient hemodynamic outcome following angiographic success and provide a hint as to further endovascular strategy.
Comprehensive approach to critical limb ischemia (CLI). Given that CLI is characterized by multifactorial disorders, a comprehensive approach tailored to each patient including not only revascularization but also foot care and infection control enables clinical success.
Amid a pandemic of peripheral artery disease, contemporary catheter-based intervention is a paradigm shift in the treatment of symptomatic infrapopliteal artery disease. From a clinical perspective, the increasing popularity of infrapopliteal intervention heightens the importance of proactive wound management as stand-alone endovascular procedure does not necessarily facilitate clinical success following procedural success (Figure 8). Therefore, harmonization of revascularization and wound management in a coordinated approach is indispensable in the treatment of CLI.
Comparison of restenosis rates reported in recent studies.39,40,41,43–45
