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1746 KOBAYASHI N et al. Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Peripheral Vascular and Wound Location in Critical Limb Following Endovascular Treatment Norihiro Kobayashi, MD; Keisuke Hirano, MD; Masatsugu Nakano, MD, PhD; Toshiya Muramatsu, MD; Reiko Tsukahara, MD, PhD; Yoshiaki Ito, MD; Hiroshi Ishimori, MD, PhD

Background: The differences in according to wound location remain unclear.

Methods and Results: Between April 2007 and October 2011, 138 patients (166 limbs) with critical limb ischemia with loss were treated with endovascular treatment. On these limbs, 177 individual were identified on the foot and were evaluated for wound healing rates and time to healing according to their locations. Wound locations were divided into 3 groups: group T (Toe wounds, n=112), group H (Heel wounds, n=25), and group E (Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces, n=40). The mean follow-up pe- riod was 23±19 months. At 3, 6, 9, and 12 months, wound healing rates were 51%, 64%, 75%, and 75%, respec- tively, in group T; 12%, 36%, 36%, and 52%, respectively, in group H; and 0%, 5%, 8%, and 13%, respectively, in group E. The median time to healing was 64 days (interquartile range 25–156 days) in group T, 168 days (interquar- tile range 123–316 days) in group H, and 267 days (interquartile range 177–316 days) in group E (P=0.038).

Conclusions: Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces were the most difficult type of wound to heal. (Circ J 2014; 78: 1746 – 1753)

Key Words: Critical limb ischemia; Time to wound healing; Wound healing rate; Wound location

ndovascular treatment (EVT) has recently been consid- ered as an acceptable treatment for critical limb isch- Methods E emia (CLI), in addition to surgical , Patients particularly in patients with many comorbidities.1–10 Previous We performed EVT to treat 895 patients (1,395 limbs) with studies have reported that the major rate for CLI peripheral disease; this was the primary treatment used after EVT was 10.5–25%.6,7,11,12 To avoid major amputation, in our institute from April 2007 to October 2011. Of these, 154 “wound healing” is a very important endpoint, although many patients (182 limbs) had non-healing ulcers or clas- earlier reports have focused largely on vessel patency, limb sified as Rutherford 5 or 6 and were treated by EVT. A total of salvage, and mortality rates, with insufficient evaluation as to 198 separate wounds were identified in these limbs. Ten of whether wounds were completely healed. Although some data these wounds were excluded because of their small number (3 are available on wound healing rates and time to healing after being located only on the shin, 5 located only on the ankle, and surgical revascularization or EVT,8,11,13–18 these reports exam- 2 small wounds located only on the surface of the dorsum of ined wound healing rates according to limb rather than indi- the foot). Furthermore, 9 of the limbs (5.2%) receiving addi- vidual wounds. Sometimes, several wounds exist on 1 limb; tional surgical revascularization (6 distal bypass and 3 femo- thus, each wound should be evaluated separately. Furthermore, ropopliteal bypass) were excluded; therefore, eventually, 138 the locations of wounds are only occasionally evaluated as an patients, 166 limbs, and 177 individual wounds were included. important factor influencing the healing rate. It has been re- Although we discussed the indications of bypass with vascular ported that heel ulcers and gangrene are difficult to treat and surgeons, a number of patients were inoperable because of the often lead to major amputation.11,14,19,20 However, in clinical high surgical risk and severe diffuse calcification of the distal practice, difficulty is experienced in treating wounds extending artery. The study protocol was developed in accordance with onto the fore- or mid-foot along the dorsal or plantar surfaces. the Declaration of Helsinki, with all patients providing written The aim of this study was thus to evaluate the healing of each informed consent prior to enrollment. wound according to its location in CLI following EVT. The 177 individual wounds were divided into 3 groups ac-

Received February 11, 2014; revised manuscript received March 24, 2014; accepted March 27, 2014; released online May 8, 2014 Time for primary review: 16 days Department of Cardiology, Saiseikai Yokohama-city Eastern Hospital, Yokohama, Japan Mailing address: Norihiro Kobayashi, MD, Department of Cardiology, Saiseikai Yokohama-city Eastern Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8765, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-0171 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.78, July 2014 Wound Healing and Wound Location 1747

Figure 1. Classification of wound locations. (A) Wounds located only at the toes (group T). (B) Wounds located at the heel (group H). (C) Extensive wounds extending onto the fore- or mid-foot along the dorsal or plantar surfaces (group E).

cording to their location (Figure 1). Group T (toe) comprised plus ticlopidine (200 mg/day), or clopidogrel (75 mg/day) was wounds localized only to the toes, group H (heel) comprised administered to all patients before the procedures and contin- wounds localized to the heel, and group E (extensive) com- ued for at least a month. prised extensive wounds extending onto the fore- or mid-foot along the dorsal or plantar surfaces. Wound healing rates and Follow-up and Wound Care time to healing were retrospectively analyzed. The mean follow-up period was 23±19 months. Patients were followed up at our outpatient foot care clinic after EVT until Patient Evaluation and Intervention Procedure their wound was completely healed. If patients did not attend On admission, an interventional cardiologist and plastic sur- the clinic, we called them to ask about the status of the wounds geon checked the location and extent of tissue loss, and images and made a further appointment at the foot care clinic on a dif- of all wounds were captured to compare the course of healing. ferent day. However, 11 patients (7%) were lost to follow up The patient’s lower limb (femoral, popliteal, dorsalis, because of transferring to other hospitals or losing contact. We and posterior tibial artery) were palpated, and the hemody- took pictures of the wounds each time, with the time of wound namic status was evaluated using the ankle brachial index healing being recorded. Wound healing was based on the (ABI), skin pressure (SPP), and duplex ultrasound. TIME classification (Tissue, or , Mois- SPP was measured on the dorsal and plantar sides of the foot. ture imbalance, and Edge of wound).21 After wound healing, Flow in the lower limb artery was evaluated routinely before the patients were monitored by clinical assessment every 3 EVT using duplex ultrasound and digital subtraction angiogra- months. Our management included cleaning of the wounds, phy (DSA). The indications for EVT were decided after dis- application of ointment, wound debridement, use of vacuum- cussions with vascular surgeons. assisted closure therapy (VAC; Kinetic Concepts, San Antonio, A retrograde approach was generally used for treatment of TX, USA),22,23 and education of patients and families with re- iliac lesions. A 6-Fr sheath was inserted into the ipsilateral gard to daily care of wounds. Enzymatic ointments were ap- common and a 0.014-inch or 0.018-inch wire plied if necessary, as per the plastic surgeon’s discretion. In was advanced into the lesion under intravascular ultrasound addition, off-loading techniques were employed using custom- (IVUS) guidance. After pre-dilatation using an optimal size of ized shoes for the purpose of depressurization. Infectious balloon, primary stenting using a self-expandable stent was wounds were treated by using appropriate , and if performed. The correct balloon and stent diameter was deter- infection was not resolved sufficiently, myelitis or subcutane- mined by IVUS. For treating femoropopliteal lesions, the ma- ous abscesses was investigated using magnetic resonance im- jority of cases were treated by an antegrade approach through aging or duplex ultrasound. If necessary, incisional drainage the contralateral common femoral artery. A 6-Fr sheath was and ostectomy were added or an auto skin and free flap used and a 0.014-inch wire was advanced into the lesion. Bal- reconstruction were performed by a plastic surgeon. We eval- loon angioplasty using a balloon with a diameter 1–2 mm less uated ABI or SPP every 3 months for all patients, and duplex than the reference diameter was performed for 120–180 s. If ultrasound was performed when ABI or SPP values suggested the patients had a residual pressure gradient of >10 mmHg, an abnormality and delay in wound healing. However, we do residual diameter of >30%, and/or flow-limiting dis- not necessarily perform an if wound healing is section after balloon angioplasty, a self-expandable stent was favorable, even though ABI, SPP and duplex values suggest implanted. For treating infrapopliteal lesions, generally a 4-Fr restenosis. After angiographical restenosis was evident, we sheath was inserted into the ipsilateral common femoral artery performed repeat intervention for only the wounds with de- for an antegrade approach. A 0.014-inch wire was then ad- layed healing. Repeat intervention was performed until wound vanced into the lesion and only balloon angioplasty was per- healing was achieved. If this intervention failed, the vascular formed. Patients always received 5,000 U after sheath surgeon was requested to perform surgical revascularization. insertion. Dual antiplatelet therapy of aspirin (100 mg/day)

Circulation Journal Vol.78, July 2014 1748 KOBAYASHI N et al.

Table 1. Baseline Characteristics of the 138 Critical Limb Ischemia Patients Group T Group H Group E P value (n=84) (n=17) (n=37) Age (years) 73±10 73±8 71±13 0.63 Gender (male) 54 (64%) 14 (82%) 20 (54%) 0.42 Body mass index 22±4 20±3 20±3 0.08 Risk factors/comorbidities Hypertension 69 (82%) 14 (82%) 29 (78%) 0.88 Dyslipidemia 28 (33%) 5 (29%) 14 (38%) 0.81 mellitus 60 (71%) 14 (82%) 29 (78%) 0.53 Insulin use 21 (25%) 4 (24%) 13 (35%) 0.48 Dependence on hemodialysis 32 (38%) 6 (35%) 23 (62%) 0.036 history 35 (42%) 5 (29%) 16 (43%) 0.60 27 (32%) 8 (47%) 16 (43%) 0.33 23 (27%) 4 (24%) 11 (30%) 0.89 EF 57±12 57±13 56±13 0.91 Low EF <40% 9 (11%) 2 (12%) 5 (14%) 0.92 Non-ambulatory status Wheelchair 22 (26%) 8 (47%) 12 (32%) 0.12 Bedridden 3 (4%) 0 (0%) 4 (11%) 0.15 Laboratory data Albumin g/dl 3.3±0.5 3.0±0.5 2.8±0.7 <0.001 C-reactive protein mg/dl 2.0±1.7 2.6±1.6 5.2±2.1 <0.001 White blood cell /μl 7,300±2,100 6,900±3,000 9,400±4,500 0.001 Creatinine mg/dl 3.3±2.5 3.3±2.1 4.6±3.5 0.18 Hemoglobin A1c % 6.8±1.7 6.8±1.4 6.6±1.4 0.73 Medications Cilostazol 58 (69%) 12 (71%) 17 (46%) 0.04 Group T, toe wounds; Group H, heel wounds; Group E, extensive wounds extending onto the fore- or mid-foot along the dorsal or plantar surfaces; EF, Ejection fraction.

Table 2. Lesion Characteristics and Endovascular Procedures of 177 Individual Wounds Group T Group H Group E P value (n=112) (n=25) (n=40) Location of target lesion Aortoiliac 0 (0%) 0 (0%) 0 (0%) Femoropopliteal 3 (2.7%) 2 (8%) 0 (0%) 0.16 Infrapopliteal 68 (60.6%) 12 (48%) 21 (52.5%) 0.47 Aortoiliac+Femoropopliteal 2 (1.8%) 1 (4%) 0 (0%) 0.47 Aortoiliac+Infrapopliteal 5 (4.5%) 2 (8%) 2 (5%) 0.77 Femoropopliteal+Infrapopliteal 28 (25%) 5 (20%) 14 (35%) 0.34 Aortoiliac+Femoropopliteal+Infrapopliteal 6 (5.4%) 3 (12%) 3 (7.5%) 0.48 Proportion of infrapopliteal 106 (95%) 22 (88%) 40 (100%) 0.10 Chronic total occlusion (length >200 mm) 48 (43%) 11 (44%) 30 (75%) 0.03 Lesion calcification* 39 (35%) 13 (52%) 25 (63%) 0.007 Infection 38 (34%) 12 (48%) 33 (83%) <0.001 Gangrene 45 (40%) 17 (68%) 33 (83%) 0.001 Treatment outcomes One straight line to the foot 102 (91%) 23 (92%) 26 (65%) <0.001 Direct blood flow to the wounds 82 (73%) 19 (76%) 20 (50%) <0.001 ABI before EVT 0.67±0.23 0.51±0.15 0.56±0.15 0.06 ABI after EVT 0.89±0.16 0.81±0.13 0.87±0.12 0.45 SPP before EVT mmHg 22±11 19±9 20±9 0.10 SPP after EVT mmHg 53±23 52±22 53±19 0.15 Repeat EVT 29 (26%) 9 (36%) 12 (30%) 0.61 ABI, Ankle brachial index; EVT, endovascular treatment. Group T, toe wounds; Group H, heel wounds; Group E, exten- sive wounds extending onto the fore- or mid-foot along the dorsal or plantar surfaces; SPP, Skin perfusion pressure. *Defined as an obvious calcified vessel wall, assessed by angiography.

Circulation Journal Vol.78, July 2014 Wound Healing and Wound Location 1749

Figure 2. Wound healing rates according to wound locations.

Figure 3. Comparison of 1 straight line rates, direct blood flow rates, and wound healing rates between the 3 groups.

Endpoints not be obtained due to intractable rest or a non-compress- The primary endpoint of this study was the wound healing rate ible artery due to severe calcification, SPP was measured at the and the secondary endpoint was time to wound healing. dorsum and sole of the foot. An SPP of <40 mmHg was de- fined as ischemic tissue loss or rest pain.24 Technical success Definitions was defined as achievement of at least 1 straight line to the Ischemic tissue loss due to CLI was defined according to the foot with <30% residual stenosis in the target lesion without Trans Atlantic Inter-Society Consensus (TASC) guideline as any obvious flow-limiting lesions.25 One straight line included tissue loss associated with an ankle pressure of <70 mmHg or collateral flow from the peroneal artery to the distal tibial ar- a toe pressure of <50 mmHg.2,3 If these measurements could tery. Direct blood flow to the wound was defined as achieve-

Circulation Journal Vol.78, July 2014 1750 KOBAYASHI N et al.

Figure 4. Median time to healing in com- pletely healed wounds according to wound locations.

ment of adequate blood flow to the wound evaluated by DSA tically significant. All analyses were performed by using SPSS after EVT in addition to the 1 straight line to the foot, irrespec- software (version 19; IBM Corporation, Somers, NY, USA). tive of the use of the angiosome concept.26 We defined time to healing as the time needed to achieve complete epithelializa- tion of the ischemic lesions, with all wound care becoming Results unnecessary including wound cleaning and application of oint- Patient Characteristics ment. An infectious wound was defined by the use of any an- This study included 138 patients (88 males, mean age 71±10 tibiotic during the course of a disease, excluding prophylactic years), 166 limbs, and 177 individual wounds treated by only purposes. Toe or transmetatarsal were considered EVT. Group T included 112 wounds, group H included 25 minor amputations, whereas major amputation included all wounds, and group E included 40 wounds. There were no above-ankle amputations. Wounds were left open after minor significant differences between the 3 groups except for albu- amputation, and wound treatment to achieve the growth of min (Alb), C-reactive (CRP) levels, white blood granulation was performed. Thus, time to healing after minor (WBC), rates of hemodialysis, and cilostazol administration. amputation was also defined as complete epithelialization of As shown in Table 1, Alb was lower in group E than in the the ischemic lesions, with no further need of wound care, in- other 2 groups (group T, 3.3±0.5 g/dl; group H 3.0±0.5 g/dl; cluding wound cleaning and ointment application. Coronary group E 2.8±0.7 g/dl; P<0.001), the corresponding CRP and artery disease was defined as documented pectoris, WBC values were higher in group E than in the other 2 groups myocardial , or a history of coronary artery revascu- (CRP: group T 2.0±1.7 mg/dl, group H 2.6±1.6 mg/dl, group larization, and cerebrovascular disease as a history of , E 5.2±2.1 mg/dl; P<0.001; WBC: group T 7,300±2,100 /μl, transient ischemic attacks, carotid artery revascularization, or group H 6,900±3,000 /μl, group E 9,400±4,500 /μl; P=0.001). . Non-ambulatory status was defined Rates of hemodialysis were higher in group E than in the other as being wheelchair-bound or in a bedridden state. 2 groups (38%, 35%, and 62%, respectively, P=0.036). Cilo- stazol administration rates were 69%, 71%, and 46%, respec- Statistical Analysis tively (P=0.04). The analysis was on an intention-to-treat basis. Continuous vari- ables with normal distributions were expressed as mean ± stan- Lesion Characteristics and Endovascular Procedures dard deviation, whereas variables without normal distribution There were no significant differences in the location of the were expressed as median and interquartile range (namely, target lesions in groups T, H, and E (Table 2). The majority of wound healing time). Categorical variables were shown as patients had infrapopliteal lesions (group T 95%, group H 88%, percentages. Comparisons of more than 2 groups were tested by and group E 100%, respectively). The corresponding percent- using 1-way analysis of variance or the Chi-squared test, where- ages for chronic total occlusion (CTO) lesions longer than as multiple comparisons were performed by using Tukey’s 200 mm for each group (T, H, E) were 43%, 44%, and 75%, honestly significant difference test. Univariate analysis was respectively (P=0.03). The lesion calcification was significant- performed to identify factors that predicted wound healing, and ly severe in group E (group T 35%, group H 52%, and group Cox proportional hazard analysis was used to identify the inde- E 63%, respectively, P=0.007). The rates of 1 straight line to pendent predictors of wound healing. Kaplan-Meier analysis the foot for groups T, H and E were 91%, 92%, and 65%, re- and the log-rank test were used to compare groups for wound spectively, (P<0.001), and the rates of direct blood flow to the healing rates. A 2-sided P value of <0.05 was considered statis- wound were 73%, 76%, and 50%, respectively (P<0.001). In-

Circulation Journal Vol.78, July 2014 Wound Healing and Wound Location 1751

Table 3. Multivariate Cox Proportional Hazard Analysis for Wound Healing After Endovascular Therapy for Critical Limb Ischemia Hazard ratio 95% CI P value Extensive wounds extending onto the fore- or mid-foot along 0.17 0.07–0.40 <0.001 the dorsal or plantar surfaces Dependence on hemodialysis 0.33 0.21–0.51 <0.001 Heel wounds 0.39 0.22–0.71 0.002 Infectious wounds 0.65 0.42–0.99 0.046 Direct blood flow to the wounds 1.90 1.12–3.24 0.018

fection and gangrene rates were higher in group E than in the other 2 groups (group T and H; infection; group T 34%, group Discussion H 48%, and group E 83%, P<0.001; gangrene: group T 40%, Occasionally, there are several wounds on limbs of patients group H 68%, and group E 83%, P=0.001). Both ABI and SPP with CLI, and each of their healing courses are different. In a improved and were similar in all 3 groups after EVT (ABI: typical case, 1 wound could be healed but the other wound group T 0.89±0.16, group H 0.81±0.13, and group E 0.87±0.12; could not, meaning that as a result, the patient must undergo P=0.45; SPP: group T 53±23 mmHg, group H 52±22 mmHg, major amputation or die. In such a case, wound healing could and group E 53±19 mmHg; P=0.15). The rate of repeat EVT not be obtained for the limb, however, one wound would be was also similar in the 3 groups (group T 26%, group H 36%, successfully healed. Therefore, it is important to investigate and group E 30%; P= 0.61). the factors that influenced wound healing between these 2 wounds. The important thing is that wound healing should be Wound Healing assessed by “each wound” and not by each limb. The same is At 3, 6, 9, and 12 months, wound healing rates were 51%, 64%, true for CLI patients with both legs’ tissue loss. 75%, and 75%, respectively, in group T; 12%, 36%, 36%, and This study revealed that the wound healing rate of extensive 52%, respectively, in group H; and 0%, 5%, 8%, and 13%, wounds extending onto the fore- or mid-foot along the dorsal respectively, in group E. Kaplan-Meier analysis showed sig- or plantar surfaces were the lowest. The biggest factor of nificant differences in the wound healing rates in the 3 groups wound non-healing in extensive wounds was poor achieve- (group T vs. group H, P=0.019; group H vs. group E, P=0.007; ment rate of direct blood flow to the wounds. We achieved group T vs. group E, P<0.001; Figure 2). In addition, a larger 50% direct blood flow to the wound in group E, but this rate discrepancy was observed between direct blood flow rates and was statistically significantly lower than that in the other 2 wound healing rates in group E than compared with the other groups. In our opinion, this result can be derived from the fact groups (direct blood flow rates; 50%, and wound healing rates; that group E had more severe target lesion characteristics. The 13%; Figure 3). incidence rates of CTO lesions >200 mm and lesion calcifica- The median time to healing in completely healed wounds tion were statistically significantly higher in group E. In the was 64 days (interquartile range 25–156 days) in group T, 168 BASIL study that compared balloon angioplasty with bypass days (123–316 days) in group H, and 267 days (177–316 days) ,27 it revealed favorable results for bypass surgery in in group E (group T vs. group H, P<0.001; group H vs. group patients with CLI; however, the BASIL study was conducted E, P=0.49; Figure 4). Minor amputation was performed for 35 with the exception of unsuitable patients for bypass surgery. wounds in group T (31%), 13 wounds (33%) in group E, and In contrast, the present study included all CLI patients with none in group H. The incidence of major amputation and death non-healing ulceration or gangrene, irrespective of whether before achieving complete healing during the follow-up period revascularization succeeded. Of these, there were numerous were 6 limbs (5.7%) and 24 patients (28.6%) in group T, 2 inoperable cases because of the high risk of surgery and severe limbs (9.5%) and 5 patients (29.4%) in group H, and 19 limbs diffuse calcification of the distal artery. These patients had no (47.5%) and 24 patients (64.9%) in group E. choice but to be treated by intervention, although the effects were limited. In fact, this is the actual scenario in our Predictors of Wound Healing clinical settings, and we cannot ignore these patients in day-to- Univariate analysis showed that diabetes mellitus (DM), de- day clinical practice; therefore, we must evaluate wound heal- pendence on hemodialysis (HD), non-ambulatory status, CRP, ing rates, including those for wounds that are difficult to treat. Alb, infectious wound, extensive wounds extending onto the A large discrepancy was observed between direct blood flow fore- or mid-foot along the dorsal or plantar surfaces, heel rates and wound healing rates in group H and group E, imply- wounds, gangrene, and direct blood flow to the wounds were ing that some wounds in group H and group E did not heal associated with wound healing. Of these factors, multivariate successfully despite achievement of direct blood flow to the Cox proportional hazard models revealed that dependence on wounds. On the contrary, the wound healing rate was higher HD (hazard ratio [HR] 0.33, 95% CI 0.21–0.51, P<0.001), in- than the direct blood flow rate in group T. A reasonable inter- fectious wounds (HR 0.65, 95% CI 0.42–0.99, P=0.046), exten- pretation of these discrepancies is that success of revascular- sive wounds extending onto the fore- or mid-foot along the ization is not the only factor that predicts wound healing. Al- dorsal or plantar surfaces (HR 0.17, 95% CI 0.07–0.40, P<0.001), though there are few published studies investigating predictors and heel wounds (HR 0.39, 95% CI 0.22–0.71, P=0.002) were of not only limb salvage or death, but also of “wound healing,” negative predictors of wound healing; furthermore, direct blood Iida et al.28 reported that a body mass index (BMI) of <18.5 flow to the wounds (HR 1.90, 95% CI 1.12–3.24, P=0.018) was (HR, 0.54; P=0.03) and wound infection (HR, 0.60; P=0.04) positive predictor of wound healing (Table 3). were predictors of unhealed wounds. Furthermore, Kawarada et al.18 reported that DM, infectious wounds, and pedal arch

Circulation Journal Vol.78, July 2014 1752 KOBAYASHI N et al. classification were independent predictors of wound non-heal- clinical course of patients with CLI treated by EVT alone. In ing. In this study, multivariate Cox proportional hazard analy- addition, although wound care is very important, usually there sis revealed that extensive wounds extending onto the fore- or is no discussion regarding the type of treatment administered. mid-foot along the dorsal or plantar surfaces, heel wounds, To improve wound healing rates in patients with CLI, estab- infectious wounds, and dependence on HD were independent lishment of effective treatment strategies and standardization predictors of non-healing wounds. These findings suggest that of wound treatment is necessary. evaluation of wound locations is meaningful for the prediction Group E patients had a poor baseline background (DM: 78%, of wound healing. HD: 62%; infection: 83%, gangrene: 83%) and an extremely Ulceration or gangrene located at the heel is considered dif- poor wound healing rate (only 13%) in this study. In addition, ficult to treat, and it has been recommended to carry out pri- these patients had a high rate of major amputation (47.5%) and mary amputation in selected individuals with heel .29,30 death (64.9%) before achieving complete wound healing. EVT Soderstrom et al.20 showed that ischemic tissue lesions located has limitations in the treatment of such patients, and bypass on the mid- and hind-foot had significantly prolonged ulcer surgery should be considered if their general condition is fair healing times (HR 0.4, P=0.044). In contrast, Berceli et al.14 and there are sufficient distal arteries to connect bypass. Exten- showed that complete healing rates for forefoot and heel lesions sive wounds always develop from smaller wounds such as toe were similar (90.5% vs. 86.5%, P=0.26), with comparable rates wounds; therefore, it is essential to diagnose CLI patients with for major lower extremity amputation (9.8% vs. 9.3%, P=0.87). tissue loss at an earlier stage and perform revascularization and Dosluoglu et al.19 reported that 24-month limb salvage and provide appropriate wound care as soon as possible to prevent patency rates were similar between patients with heel ulcers or wound growth. Furthermore, for these extensive wounds from gangrene and those with lesions on other parts of the foot. Our patients with poor background characteristics such as depen- findings are in agreement with those of Soderstrom et al., and dence on HD or wound infection, it might be necessary to they indicate that the rate of healing of heel wounds was lower consider primary amputation, if we cannot achieve successful than that of toe wounds, and that it took a considerably longer revascularization or if there are no signs of wound healing fol- time to heal. We consider that heel wounds, which tend to be lowing successful revascularization. larger than toe wounds, get compressed easily while walking and sleeping, leading to a further delay in wound healing. Fur- Study Limitations thermore, the rate of infection and gangrene was higher in This study had several limitations. First, it was a non-random- group H than in group T. These factors might influence each ized, retrospective analysis at a single center, with a relatively other and might cause a delay of healing of heel wounds. small sample size. Second, evaluation of the severity of each Minor amputations were performed for 35 wounds in group wound was insufficient. The Texas University classification T (31%) and 12 wounds (30%) in group E; however, none and Wegner’s classification have been established for evalua- were performed in group H. Some reports suggested the use of tion of the diabetic foot.35 These classifications include assess- minor amputation for the treatment of large ulcers or gan- ment of ulcer size, wound appearance, clinical evidence of grene.31–33 After optimal minor amputations, we could achieve infection, ischemia, and neuropathy. The size and depth of wound healing more easily and also shorten the time of heal- wounds were not considered in this study. Third, we could not ing for large wounds such as wounds extending onto the fore- completely follow the patency rates of the treated vessels. or mid-foot along the dorsal or plantar surfaces. Minor ampu- Finally, the strategy of infrapopliteal angioplasty was limited tations were performed for all healed wounds in group E in this to only balloon angioplasty as other options such as bare- study. In contrast, Bollinger and Thordarson found that partial metal stents, drug-eluting stents, drug-coated balloons, and calcanectomy was a good alternative to below-knee amputa- laser atherectomy were not available in Japan. In this regard, tion.32 Although we could not perform minor amputations for a reduction of target lesion revascularization has been reported heel wounds, it might be possible that a partial calcanectomy with the use of drug-eluting stents36–38 or laser atherectomy.39 for heel wounds refractory to conservative therapy might im- prove the rate of wound healing and reduce the healing time. In the clinical setting, we generally divide wounds into 2 Conclusions groups using the Rutherford classification, that is, into Rutherford Extensive wounds extending onto the fore- or mid-foot along 5 or Rutherford 6. However, the Rutherford classification is the dorsal or plantar surfaces had the lowest healing rates and ambiguous and sometimes it is difficult to clearly categorize the longest time to healing compared with other types of wounds into 2 groups because there are various types of wounds. It is difficult to achieve direct blood flow to these wounds and sometimes multiple wounds on 1 limb. In the pres- extensive wounds because of their severe target lesion. In ad- ent study, we divided wounds into 3 groups according to their dition, patients who belonged to group E were apparently in a locations, and revealed statistically different results of wound poor condition in terms of wound healing due to low albumin- healing rates, although there were differences in baseline char- emia, high CRP, and high WBC. These factors were all related acteristics. Multivariate analysis revealed that extensive wounds to hemodialysis, so not only wound location but also the patient extending onto the fore- or mid-foot along the dorsal or plan- background, especially if they are being treated with hemodi- tar surfaces and heel wounds were independent predictors of alysis, have a great impact on wound healing. Heel wounds wound non-healing. Thus, a different classification system also exhibited a poor healing rate and took a considerably that includes detailed information of wound characteristics longer time to heal compared with toe wounds. Multivariate might be needed. Azuma et al.34 reported wound healing rates analysis revealed that wounds extending onto the fore- or mid- in patients with CLI after bypass surgery using a similar cat- foot along the dorsal or plantar surfaces and heel wounds were egorization (Rutherford 5, Rutherford 6 with heel ulcer or an independent adverse predictor of wound healing, as factor gangrene, Rutherford 6 without heel lesion). In our study, we of wound locations as well as hemodialysis and wound infec- divided wounds more specifically into 3 types, with respect to tion. Apart from successful revascularization, various factors wound locations, and included only patients treated by EVT including patient background and wound characteristics are alone. Thus, this is a meaningful study in the evaluation of the associated with wound healing; therefore, we should treat not

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Circulation Journal Vol.78, July 2014