Below-the-Knee Revascularization of Critical Limb Ischemia in Diabetic Patients

The establishment of a guide for the prevention, diagnosis, and treatment of diabetic foot (DF) and CLI is essential to address its management in the most cost-effective way. Between the appearance of an ulcer and the amputation of the limb, there should be treatment that should be rational, regulated, and economical as to avoid the loss of the limb. Especially, when we know that a quarter of patients with diabetes mellitus (DM) will develop an ulcer; 85% of major amputations in diabetic patients are preceded by an ulcer; 65% of ulcers have an ischemic component, and peripheral arterial disease (PAD) has a prevalence of 10%-40% among patients with DM. Additionally, ischemic ulcers have a high recurrence rate and double amputation rate than that of DM and PAD, which have a mortality of five years close to 50% (higher than many forms of cancer) and finally, the mortality of patients with PAD and DM, who suffer an amputation, is 50% at two years.^1,2,3 

Microvascular involvement, caused by both neuropathy and infection, causes the healing of the lesion to have a worse evolution than the non-diabetic patient in a situation of CLI. Despite the knowledge we have about the pathophysiology of DF and the recommendations that the authors made in 1982 when the guide for the treatment of CLI was created, the recommendations elaborated were not applicable to the patient with DM; however, in the 30 years since it has been the only guide used for the management of DF by many vascular surgeons.⁴  

The Rutherford classification system has no value in the study of DF. Despite this, most studies published to date that analyze DF revascularization use it in the gradation of ischemia. Both the Fontaine and Rutherford classification systems report the presence or absence of an injury; however, they do not address a very important factor: whether or not there is an infection, as well as the extent, location, and depth of said infection. It is known that deeper lesions have a longer healing time, as well as a lower rate of healing, with a worse rate of limb salvage; what leads to an amputation in the diabetic patient is not only ischemia but also the infection itself.

The TASC classification for the treatment of PAD emphasizes the severity of the arterial injury, rather than the trophic injury itself. The cure rate is not the stated objective of the TASC when evaluating the efficacy of endovascular therapy in critical ischemia of the lower limb. The management of CLI is not completed only by treating ischemia; wound care, including control of the infection as well as treatment of the tissue defect after revascularization, is imperative. It is evident that the arterial insufficiency of the diabetic foot is not the only point of focus for its treatment. The severity of PAD makes it possible to understand, in part, the limitations of the healing of the trophic lesion, but it is not the only factor. Poor glycemic control, infection, the coexistence of other co-morbidities (with special attention to end-stage renal disease), microvascular dysfunction, inadequate topical treatment of the ulcer, poor development of collateral circulation, and the presence of the lesion in loading areas are other factors that negatively influence the healing of the lesion.^5,6 

Currently there is no scientific evidence to indicate which procedure is ideal for the revascularization of CLI/DF resulting from infrapopliteal arterial involvement. Firstly, because there is no randomized study (RCT), and secondly, because any meta-analysis carried out has the drawback indicated above (that there is a lack of rigor in the evaluation of the type of injury presented by the population under study). When we are comparing two revascularization techniques in patients with a Fontaine IV degree or a Rutherford 5 degree, to which of the different grades of the WIfI (Wound Ischemia Foot Infection) or the University of Texas classifications does it correspond? Is an exposure of the calcaneus the same as a superficial lesion without exposure of the osteo-tendinous apparatus? How can we compare surgical versus endovascular treatment by assessing the rate of healing if we are treating different trophic injuries? 

In 2016, the International Working Group on the Diabetic Foot (IWGDF) published a meta-analysis of revascularization in diabetic patients with PAD: of 56 studies analyzed, the wound healing rate is only reflected in seven, and the presence or absence infection is reported in no more than two.⁷

Endovascular approach in the infrapopliteal segment 

In recent years, endovascular treatment has taken on an increasingly important role, since it is associated with less morbidity than surgery and the industry has expanded and improved the therapeutic arsenal. However, this change in the revascularization of the limb does not have scientific evidence and there is reasonable doubt about the duration of the angioplasty.⁸ It is evident that endovascular treatment in the infrapopliteal sector has been gaining a more preponderant role. With the "endovascular first" strategy, the open revascularization is being cornered — recent evidence indicates that percutaneous treatment of foot artery disease improves clinical outcomes in patients with CLI.^9-14 Manzi et al reported an initial experience with the pedal plantar loop technique with positive clinical results at acute and mid-term follow-up.¹⁰

Troisi et al demonstrated that the pedal arch status has a positive impact on healing time, limb salvage, and survival in diabetic patients with foot wounds undergoing infrainguinal endovascular revascularization.¹⁵

Nakama et al demonstrated that patients with CLI and pedal artery disease who underwent pedal artery angioplasty showed a higher rate of wound healing and a shorter healing time. The main limit of these studies is that there is no clear mention of the outflow into small foot arteries.¹⁴

However, the endovascular approach is not always achieved. Faglia et al published a large series of 993 diabetic patients with trophic lesion or rest pain treated consecutively by endovascular procedure. Angioplasty was not technically possible in 16% due to the extreme calcification of the vessel that prevented the balloon from crossing the lesion.^16,17 In another series of 100 consecutive patients in which they were considered good candidates for the performance of an endovascular treatment, 11% required the completion of a bypass after a failed attempt of percutaneous angioplasty.¹⁸ 

In May 2018, Ferraresi et al published a retrospective study of 1915 limbs dividing 1613 PAD patients on two different stages: big artery disease (BAD) and small artery disease (SAD), and how this concept should not be confused with diabetic microangiopathy. They conclude SAD is strongly associated with DM and dialysis.¹⁹

Probably if we understand these scenarios about CLI and the failure of the distribution system of the foot, it will allow us to better stratify patients, and evaluate in more detail the effect of endovascular approaches and open surgery.

A key point in the infrapopliteal revascularization of patients with trophic lesions is the treatment of the tibial arteries following the angiosome concept. The most beneficial effect has been observed in patients with diabetes and with renal failure.²⁰ The studies that have been performing revascularization by means of a bypass following the angiosome concept suggest that better healing of trophic lesions depends more on the presence of a plantar arch than on direct revascularization following the angiosome. However, the characteristics of the plantar arch did not influence graft permeability or amputation rates. The location and extension of ischemic lesions, as well as comorbidities, are more relevant to wound healing than revascularization guided by the angiosome.^21,22 

Varela et al demonstrated that ulcer blood flow restoration though collateral vessels may give similar results to those obtained through its specific source artery, and Kawarada et al demonstrated that “single tibial artery revascularization, whether of the anterior or posterior tibial artery, yielded comparable improvements in microcirculation of the dorsal and plantar foot. Approximately half of the feet revascularized had a change in microcirculation that was not consistent with the 2D angiosome theory.”^23,24

Two meta-analyses carried out to compare direct endovascular revascularization (following the angiosome concept) versus indirect endovascular revascularization have similar limitations: (1) they are prepared by retrospective studies in one case and with only two prospective studies in the other; (2) heterogeneity of the patients’ characteristics and of the clinical results; (3) the absence of arteriography of the foot; (4) no correct assessment of the trophic lesions; and (5) the control cases (indirect revascularization) most likely correspond to historical cases. Biancari suggests this could improve wound healing after direct revascularization.²⁵ However, Simpio et al make an analysis of the literature published up to 2013 and concludes that there is limited evidence that could maintain the revascularization model guided by the angiosome concept.⁸ The author acknowledges that performing a randomized study would be unethical, since the choice of the distal anastomosis of a bypass or endovascular treatment should be guided by the best surgical principles and not by the imposition of a study.

The impact of revascularization using the angiosome concept has also been evaluated by comparing endovascular versus bypass revascularization.²⁶ Open surgery obtains better healing rates than endovascular therapy, regardless of whether the bypass was performed or not following the angiosome concept. The best rate of limb salvage was achieved by revascularization performed with angiosome-guided bypass, and indirect endovascular revascularization obtained the worst limb salvage rates. This study demonstrates the benefit of angiosome-guided revascularization in both forms of revascularization. The first endovascular strategy is good when guided by the angiosome. However, revascularization by bypass, directly or indirectly, has the best rates of healing and limb salvage.

In a review of the angiosome concept in the revascularization of CLI, it was found that only 11 of 37 studies made reference to stratification of the lesion.³⁵ In 7 of the 11 studies, Rutherford classification was used and the Fontaine classification was used in 1 study. Although it was a largely diabetic population (in 8 of the 11 studies DM was present in more than 80%), the clinical assessment of the lesions was inadequate because of the absence of the location of the lesion, its extension and depth, and the absence or presence of an infection.

"Bypass first" vs "Endovascular first"

There is a certain group of patients for whom bypass is possibly the best strategy to follow. This group of patients is not exclusively constituted by the type of arterial involvement, but also by the patient's previous functional status and by the type of trophic lesion that presents. Which patients benefit from the "bypass first" strategy is something that is not currently answered by the scientific literature. 

Until now, the only RCT that compares endovascular treatment to open surgery is BASIL-1. Patients were recruited between 1999 and 2004 and the territory treated was mostly femoropopliteal, with very few infragenicular procedures, and the population is not specifically diabetic. In this study, no clinical differences were shown in the first year, although there were differences in favor of the "bypass first" group from the second year. 

The beginning of BASIL-2 was published at the beginning of 2016.²⁸ It compares not only the clinical outcomes but also the cost-effectiveness of endovascular treatment versus open surgery in patients in a situation of critical ischemia due to infrapopliteal involvement accompanied or not by disease of the supragenicular territory. The analysis is done according to the assessment made on the injuries through the PEDIS (Perfusion Extent Depth Ischemia Sensation) and WIfI (Wound Ischemia Foot Infection) classifications.^29,30 The primary endpoint is the higher amputation-free rate (defined as above the ankle) or the mortality rate from any cause.

Bypass to the arteries of the foot enjoy a more than acceptable permeability, 84% at 4 years.³¹  In the analysis performed by Pomposelli et al of 1032 bypasses performed on the Pedia artery, 92% were diabetic and in 53% the proximal anastomosis was performed on the popliteal artery.³² The rate of limb salvage was 78% at five years. In the meta-analysis conducted by the IWGDF published in 2016, the rate of salvage of the limb after performing bypass to arteries of the foot was 86% in the first year and 78% in the third year.³³

Endovascular revascularization of long segments of the femoro-popliteal territory or tibial arteries involves a higher rate of re-stenosis and therefore a higher percentage of secondary procedures. If after a failed endovascular treatment "bridges are not burned" for a subsequent bypass, we treat all types of injuries using the "endovascular first" strategy; but if this is not the case, revascularization of extensive tibial lesions should be performed by bypass to the arteries of the foot whenever possible. In a retrospective study of 75 bypasses performed on the arteries of the foot, where in 36 cases it was a secondary procedure after a failed endovascular treatment and in 39 it was the primary procedure, there were no statistically significant differences related to the rate of limb salvage or regarding the permeability of the procedure. The author of the publication acknowledges not performing retrograde procedures and thus does not injure an artery that hypothetically may be receiving an anastomosis. However, this German group has significantly lower permeabilities than those published. Primary and secondary permeabilities at one year are 58 and 61%.³⁴ On the contrary, worse rates of bypass patency and limb salvage have been published when in the same limb an endovascular revascularization has previously been performed (50% annually in both cases).³⁵ Another group recognizes an increase in secondary revascularization procedures, reaching 50% of all revascularizations performed in New England. These second procedures (regardless of whether an open revascularization or endovascular procedure was the first procedure) are associated with poorer medium-term results compared to primary bypass. Without assessing which strategy should be used, endovascular versus bypass procedure, this study focuses on the fact that every vascular surgeon must know that the failure of the first revascularization procedure affects the success of subsequent revascularizations.³⁶ 

There is currently no RCT comparing the infrapopliteal endovascular revascularization versus the bypass, the only comparison between the two revascularization techniques has to be made by comparing the meta-analysis of the two techniques. In the meta-analysis performed by Albers of 29 published series and with 12,320 distal popliteal bypass performed, of which 62% were to the Pedia artery, a primary and secondary patency of 63 and 70% and a salvage rate of tip of 77% at five years. In 15%, a complete TMJ of the foot was performed. This same group from Sao Paulo published a meta-analysis of the infrapopliteal endovascular procedure two years later and compared it with the one performed on open surgery. Although at three years there is a clear statistically significant difference in primary patency in favor of bypass, 48 vs 72%, there were no differences related to the 82% limb salvage rate.^37,38

Conclusion

The current clinical evidence does not support the policy "endovascular first" over "bypass first" unless there is an obvious reason such as the absence of a vein for its use as a bridge or the presence of important comorbidity that makes it prohibitive to perform an open surgery. Surgery is not acceptable in a fairly high proportion of the population due to the high surgical risk. It is also not possible to perform revascularization guided by angiosome because in many cases only one vessel remains permeable and the trophic lesions depend on several angiosomes. Therefore, the number of patients in whom it is possible to choose between a revascularization guided or not by the angiosome or between an open or endovascular treatment is much more limited in the real world than it might seem to "priori".

The primary end point of most studies is the permeability of arterial reconstruction and limb salvage, while for the patient the most important thing is the maintenance of ambulation and functional independence. That is why it is important to assess the postoperative "sequel" that an open surgery may leave in the face of an endovascular procedure. The Oregon group has analyzed their experience in the treatment of critical ischemia after bypass revascularization. Considering as ideal “being alive”, the maintenance of independence, mobility and the healing of the trophic lesion at six months, only 14.3% acquired the "ideal status" after carrying out the open revascularization.³⁹ 

 However, a recent study evaluating the functional status before and after revascularization in "frail" elderly patients in a situation of critical ischemia did not show that endovascular treatment improved the functional situation after treatment compared to open surgery. Moreover, six months after hospital discharge, patients who had undergone a bypass had a better functional "status".⁴⁰ The potential advantages of endovascular treatment include the absence of surgical wounds, less blood loss, lower economic cost and a shorter hospital stay. The effect of endovascular revascularization on the impact of physical status is clear and evident. The minimally invasive nature of the procedure implies that there is no physical deterioration or ambulatory functional status after it. However, the high re-stenosis rate makes us doubt the maintenance of ambulation and independence in the medium term. This would be the biggest argument for leaning towards the "endovascular first" option. Other conflicting points of endovascular treatment are the management and treatment of arterial long segments, worse hemodynamic improvement compared to surgical bypass, the possibility that unsuccessful endovascular treatment compromises the options of performing a bypass and finally if the frequent re-stenosis could compromise the results of revascularization.

In conclusion, it can be said that there is not enough data to recommend one method of revascularization over another. There is a real need to normalize demographic data, the severity of the disease, and the results of revascularization in diabetic patients with PAD and trophic injury. Both the specific characteristics of peripheral arterial disease and those of trophic injury should be taken into account. An effort is required to standardize the results of revascularization, which should include those related to wound healing. Finally, it is important not to focus on the specific result of the procedure (patency rates, re-stenosis, re-intervention, etc) and to give greater importance in describing the functional result (healing of the trophic lesion, functional status and mobility of the patient).

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. They report no conflicts of interest regarding the content herein.

Address for correspondence: Sandra Vicente, Email: svicente@fhalcorcon.es