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ABSTRACT
Background: Traditional end points, such as amputation-free survival, used to assess the clinical effectiveness of lower
limb revascularization have shortcomings because they do not account independently for wound nonhealing and
recurrence or patient survival. Wound healing process and maintenance of a wound-free state after revascularization
were not well-studied. The aim of this study was to elucidate the long-term clinical course of ischemic wounds after
revascularization. We focused on initial wound healing process as well as the maintenance of a wound-free state after
achievement of wound healing. We introduced a wound-free period (WFP; the period during which limbs maintained an
ulcer-free state) and Wound Recurrence and Amputation-free Survival (WRAFS) as parameters and tested their effec-
tiveness in evaluating clinical outcomes of limbs treated using endovascular therapy (EVT) and surgical revascularization.
Methods: The medical records of patients developing lower critical limb ischemia with tissue loss who underwent surgical
or endovascular revascularization of the infrainguinal vessels between 2009 and 2013 were reviewed retrospectively. The
risk factors for achieving wound healing and WRAFS were analyzed using Kaplan-Meier survival curves and Cox regression
model. Risk factors to prolong wound healing time (WHT) and reduce WFP were determined by the least squares method.
Results: In total, 233 patients underwent 278 limb revascularizations; 138 endovascular and 140 surgical procedures were
performed as first treatments. The proportion of healed wounds 1, 2, and 3 years after primary revascularization was
64.0%, 69.7%, and 70.5%, respectively. Significant risk factors for wound healing were an EVT-first strategy (risk ratio [RR],
2.47), congestive heart failure (RR, 2.05), and wound, ischemia, and foot infection wound grade (RR, 1.59). The mean WHT
was 143.7 days. An EVT-first strategy and wound infection contributed to significantly longer WHT. The mean WFP was
711.0 days. An EVT-first strategy, history of coronary artery disease, and dialysis dependence were associated with
significantly shorter WFPs. WRAFS at 1 and 2 years after achievement of wound healing were 76.9% and 64.2%,
respectively. Significant risk factors against WRAFS were a history of coronary artery disease (RR, 1.68), dialysis depen-
dence (RR, 2.03), and being wheel chair bound (RR, 1.64).
Conclusions: EVT revascularization was associated with longer WHT, reduced wound healing rate, and a shorter WFP
compared with surgical revascularization. wound, ischemia, and foot infection grade was associated with longer WHT
and reduced wound healing rate, but not associated with a shorter WFP. Systemic conditions such as dialysis depen-
dence, congestive heart failure, and being wheel chair bound were associated with reduced wound healing rate and
shorter WFP, presumably because they limited life expectancy. WHT and WFP are useful criteria for evaluating limb
outcomes in patients with critical limb ischemia. (J Vasc Surg 2017;-:1-9.)
Ischemic lower limb revascularization in peripheral (TLR). Clinical end points include survival, limb salvage
arterial occlusive disease has been evaluated with rate, amputation-free survival (AFS), and wound healing.
various end points. Technical end points include graft Most large-scale studies of critical limb ischemia (CLI) use
patency, restenosis, or target limb revascularization AFS as a clinical end point.1-3 However, AFS is a minimum
goal and is not always the same as a positive limb
outcome. The ideal outcome of revascularization in
From the Department of Vascular Surgery, Kokura Memorial Hospital, patients with peripheral arterial disease is complete re-
Kitakyushua; the Department of Vascular Surgery, Fukuoka Higashi Medical lief from ischemic symptoms, and in patients with
Center, Kogab; and the Department of Surgery and Science, Graduate School ischemic wounds, the primary goal is wound healing.
of Medical Sciences, Kyushu University, Fukuoka.c
Therefore, clinical evaluations of these patients should
Author conflict of interest: none.
Correspondence: Jin Okazaki, MD, PhD, Department of Vascular Surgery,
assess wound healing and the maintenance of a
Kokura Memorial Hospital, 3-2-1, Asano, Kokurakita-ku, Kitakyushu-shi, wound-free state. However, only a few studies have
Fukuoka 8020001, Japan (e-mail: okadoc2001@yahoo.co.jp). focused on wound healing,4 and the question as to
The editors and reviewers of this article have no relevant financial relationships to what kind of patients, limbs, and wounds have a risk of
disclose per the JVS policy that requires reviewers to decline review of any
delayed wound healing, and whether endovascular or
manuscript for which they may have a conflict of interest.
0741-5214
surgical revascularization (SUR) provides better limb out-
Copyright Ó 2017 by the Society for Vascular Surgery. Published by Elsevier Inc. comes still needs to be answered.5-8 Even when limbs
http://dx.doi.org/10.1016/j.jvs.2017.07.122 achieve wound healing, there is another question about
1
2 Okazaki et al Journal of Vascular Surgery
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factors. Variables with a P value of < .1 in the univariate Table III. Patient, limb, and wound outcome at 3 years
analysis were incorporated into a multivariate Cox after revascularization
regression model to obtain risk ratios (RRs) for the factors Outcome at 3 years All, EVT, SUR,
against each end point. after revascularization No. (%) No. (%) No. (%)
Continuous data were expressed as mean 6 standard Survival
deviation. The statistical difference with or without cate- Patients 118 52 66
gorical variables was analyzed using the Student test for Limbs 140 60 80
continuous data and the c2 test for categorical data. Lost limbs 11 (7.8) 7 (11.6) 4 (5.0)
Variables with a P value of < .05 were considered signif-
Wound unhealed 9 (6.4) 7 (11.6) 2 (2.5)
icant. All analysis were conducted using JMP 10.0
Wound healed 131 (93.5) 53 (88.3) 78 (97.5)
software (SAS Institute, Cary, NC).
Death
Patients 115 63 52
Limbs 138 78 60
RESULTS
Lost limbs 28 (20.2) 19 (24.3) 9 (15.0)
A total of 233 patients underwent 278 limb revasculari-
Wound unhealed 73 (52.8) 48 (61.5) 25 (41.6)
zations. Sixty patients underwent revascularizations in
both legs. The patient and limb characteristics are shown Wound healed 65 (47.1) 30 (38.4) 35 (58.3)
in Table I. The mean patient age was 72.5 years, and 64% EVT, Endovascular therapy; SUR, surgical revascularization.
of the patients were male. A total of 58% of the patients
were dialysis dependent, 71% had diabetes mellitus, 57%
had a history of ischemic heart disease, and 30% of Among the 278 limb revascularizations, 138 endovascu-
patients were wheel chair bound. All 278 limbs had lar and 140 surgical procedures were performed as first
ischemic ulcers. Wound grades according to the WIfI treatments. One hundred thirty-seven additional or
classification were 1 (31.6%), 2 (65.1%), and 3 (3.2%). repeated revascularizations in the ipsilateral limbs (TLR)
4 Okazaki et al Journal of Vascular Surgery
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Table V. Multivariate proportional hazards analysis of risk factors against wound healinga
Factor RR (univariate) P RR (multivariate) P
EVT first 2.1997 <.0001b 2.4728 <.0001b
Diabetes 1.1932 .2597 d d
History of CAD 1.1897 .2328 d d
Dialysis dependent 1.4758 .0070b 1.2176 0.2039
EF < 40% 1.6995 .0194b 2.0543 .0015b
Wheel chair bound 1.3954 .0452b 1.0832 .6558
b
Infection 1.3961 .0223 1.2567 .2056
WIfI wound grade $ 2 1.4946 .0078b 1.5934 .0086b
Heel wound 1.1300 .6253
CAD, Coronary artery disease; EF, ejection fraction; EVT, endovascular therapy; RR, risk ratio; SUR, surgical revascularization; WIfI, Wound, Ischemia, and
foot Infection.
a
Significant risk factors against wound healing were an EVT-first strategy (RR, 2.47), CHF (RR, 2.05), and WIfI wound grade (RR, 1.59).
b
Indicates statistical significance (P <. 05).
conversions and 39 repeat EVT procedures. Major am- wound healing rate included EVT-first strategy, dialysis
putations were performed on 26 limbs during the dependence, CHF, being wheel chair bound, and WIfI
observation period, and 83 of the 138 limbs (60.1%) ach- wound grade of $2.
ieved wound healing. Of the 83 limbs that achieved The proportion of healed wounds 1, 2, and 3 years after
wound healing, 10 had recurrent ischemic ulcer and primary revascularization was 64.0%, 69.7%, 70.5%,
three were amputated owing to recurrent CLI. Of the 55 respectively (Fig 1). According to the multivariate Cox
limbs that did not achieve wound healing, wound regression model, significant risk factors against wound
observation was terminated by amputation in 23 and by healing were EVT-first strategy (RR, 2.47), CHF (RR, 2.05),
death in 31, and one limb still had unhealed ulcer at and WIfI grade (RR, 1.59; Table V). The mean WHT in
3 years after primary revascularization (Table II). the subgroup of limbs that achieved wound healing
(n ¼ 196) was 143.7 days. An EVT-first strategy and wound
Technical outcome. Primary patency at 1, 2, and 3 years
infection contributed to significantly longer WHT
after revascularization was 66.1%, 59.1%, and 55.2%,
(Table VI).
respectively, in the SUR-first group and 46.8%, 44.3%,
We analyzed ischemic wound recurrence in the sub-
and 40.8%, respectively, in the EVT-first group. Secondary
group of limbs that achieved wound healing and found
patency at 1, 2, and 3 years was 85.1%, 81.2%, and 79.8%,
that the proportion of limbs free from CLI recurrence 1,
respectively, in the SUR-first group and 77.1%, 73.1%, and
2, and 3 years after wound healing was 91.7%, 86.6%,
66.0%, respectively, in the EVT-first group (data not
83.1%, respectively. We found no significant risk factor
shown).
for CLI recurrence (data not shown). WFP was also
Traditional clinical outcome. Overall survival at 1, 2, and analyzed in the subgroup of limbs that achieved wound
3 years after revascularization was 73.0%, 59.3%, and healing (n ¼ 196), and the mean was 711.0 days. Among
51.4%, respectively. According to the multivariate propor- analyzed risk factors, an EVT-first strategy, history of coro-
tional hazards analysis, significant risk factors against nary artery disease, and dialysis dependence were associ-
overall survival were dialysis dependence (RR, 2.72) and ated with significantly shorter WFPs (Table VII).
being wheel chair bound (RR, 2.09). The limb salvage WRAFS at 1 and 2 years after achievement of wound
rate at 1, 2, and 3 years after revascularization was 86.9%, healing were 76.9% and 64.2% (Fig 2). Multivariate pro-
84.4%, and 83.9%, respectively. Significant risk factors for portional hazards analysis of risk factors against WRAFS
limb loss were the EVT-first strategy (RR, 2.44), dialysis are shown in Table VIII. Significant risk factors against
dependence (RR, 3.62), and WIfI grade (RR, 3.55). AFS at 1, WRAFS were the history of coronary artery disease (RR,
2, and 3 years after revascularization was 64.4%, 53.2%, 1.68), dialysis dependence (RR, 2.03), and being wheel
and 45.5%, respectively. Significant risk factors against chair bound (RR, 1.64; Table VIII).
AFS were dialysis dependence (RR, 2.31), CHF (RR, 1.94),
and being wheel chair bound (RR, 2.36; data not shown).
DISCUSSION
Analysis of wound healing. The cumulative proportion Historically, the outcomes of patients with peripheral
of limbs that achieved wound healing at 3 years after pri- arterial disease have been evaluated primarily with
mary revascularization with or without each risk factor technical parameters such as graft patency or TLR. In
are shown in Table IV. Significant risk factors against patients with CLI, clinical limb outcome was considered
6 Okazaki et al Journal of Vascular Surgery
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Table VI. Mean wound healing time (WHT) in the sub- Table VII. Mean wound-free period (WFP) in the subgroup
group of limbs that achieved wound healing within 3 years of limbs that achieved wound healing within 3 years after
after primary revascularizationa primary revascularizationa
Factor No. WHT P Factor No. WFP P
Limbs achieved wound healing 196 143.7 Limbs achieved wound healing 196 711.0
EVT-first or SUR-first strategy EVT-first or SUR-first strategy
EVT 83 194.4 <.0001 b
EVT 83 639.7 .0127b
SUR 113 106.4 SUR 113 763.4
Diabetes mellitus Diabetes mellitus
Yes 135 148.4 .5097 Yes 135 721.5 .5263
No 61 133.3 No 61 687.7
History of CAD History of CAD
Yes 108 149.5 .5457 Yes 108 664.5 .0358b
No 88 136.6 No 88 768.2
Dialysis-dependent ESRD Dialysis-dependent ESRD
Yes 97 154.5 .3124 Yes 97 612.5 <.0001b
No 99 133.1 No 99 807.6
CHF (LVEF < 40%) CHF (LVEF < 40%)
Yes 19 183.0 .2484 Yes 19 594.5 .1007
No 170 137.4 No 170 730.4
Wheel chair bound Wheel chair bound
Yes 45 129.5 .4637 Yes 45 644.7 .1419
No 151 147.9 No 151 730.8
WIfI wound grade WIfI wound grade
1 73 128.8 .2782 1 73 714.4 .9156
$2 123 152.5 $2 123 709.0
Wound infection Wound infection
b
Yes 77 175.0 .0165 Yes 77 684.8 .3933
No 119 123.4 No 119 728.1
Heel wound Heel wound
Yes 17 139.4 .9008 Yes 17 624.2 .2781
No 179 144.1 No 179 719.3
CAD, Coronary artery disease; CHF, congestive heart failure; ESRD, end- CAD, Coronary artery disease; CHF, congestive heart failure; ESRD, end-
stage renal disease; EVT, endovascular therapy; LVEF, left ventricular stage renal disease; EVT, endovascular therapy; LVEF, left ventricular
ejection fraction; SUR, surgical revascularization; WIfI, wound, ischemia, ejection fraction; SUR, surgical revascularization; WIfI, wound, ischemia,
and foot infection. and foot infection.
a a
An EVT-first strategy and wound infection contributed to significantly An EVT-first strategy, history of CAD, and dialysis dependence
longer WHT. contributed to significantly shorter WFP.
b
Indicates statistical significance (P < .05). b
Indicates statistical significance (P < .05).
successful when the limb was rescued from major overshadowed by survival factors. Moreover, AFS also
amputation. However, the “limb salvage rate” does not does not always indicate successful limb outcomes,
always represent successful limb outcome, because a because patients may survive a long time without major
significant number of patients die before their symptoms amputation but with painful ischemic wounds.
are relieved. The achievement of wound healing is a clear-cut
Most recent studies have used AFS as a clinical indicator for evaluating the outcome of limbs with
endpoint.9,10 AFS is an excellent endpoint for evaluating ischemic wounds.11 After the establishment of
overall clinical outcome; however, it does not indepen- “completely healed foot lesion” as an improved criteria
dently assess limb outcome and survival. The uncertainty by Rutherford et al12 in 1997, investigators began to
about limb salvage in the subgroup of patients who die analyze wound healing and its predictors. The reported
before symptom relief (wound healing or pain relief) mean WHT varies from 47 to 264 days depending on the
makes the analysis of limb outcome difficult. Attempts clinical background. The suggested risk factors for failed
to determine the independent factors that affect or delayed wound healing are diabetes.6 low serum al-
limb salvage have failed because these factors are bumin level, ESRD, wound location on the heel,
Journal of Vascular Surgery Okazaki et al 7
Volume -, Number -
Table VIII. Multivariate proportional hazards analysis of risk factors against wound recurrence and amputation-free survival
(WRAFS)a
Factor RR (univariate) P RR (multivariate) P
EVT first 1.5168 .0420 b
1.3634 .1414
Diabetes 0.8640 .4959 d d
History of CAD 1.7829 .0050b 1.6873 .0155b
Dialysis dependent 2.2624 <.0001b 2.0378 .0006b
EF < 40% 1.5179 .2188 d d
Wheel chair bound 1.5934 .0418b 1.6412 .0394b
Infection 1.0304 .8857 d d
WIfI wound grade $ 2 1.1199 .5878 d d
Heel wound 1.5864 .1751 d d
CAD, Coronary artery disease; CHF, congestive heart failure; EF, ejection fraction; ESRD, end-stage renal disease; EVT, endovascular therapy; LVEF, left
ventricular ejection fraction; RR, risk ratio; WIfI, wound, ischemia, and foot infection.
a
Significant risk factors were the history of CAD (RR, 1.68), dialysis dependence (RR, 2.03), and being wheel chair bound (RR, 1.64).
b
Indicates statistical significance (P < .05).
15. Soderstorm M, Aho PS, Lepantalo M, Alback A. The influence lower extremity threatened limb classification system: risk
of the characteristics of ischemic tissue lesions on ulcer stratification based on wound, ischemia, and foot infection
healing time after infrainguinal bypass for critical leg (WIfI). J Vasc Surg 2014;59:220-334.
ischemia. J Vasc Surg 2009;49:932-7.
16. Mills JL, Conte MS, Armstrong DG, Pomposelli FB,
Schanzer A, Sidawy AN, et al. The society of vascular surgery Submitted Feb 22, 2017; accepted Jul 16, 2017.