Association of wound,ischemia,and foot infection clinical stage with frailty and malnutrition in chronic limb-threatening ischemia patients undergoing endovascular intervention

Abstract

Objective

The Wound, Ischemia, and foot Infection (WIfI) clinical stage has been thought to have a prognostic value in Chronic limb-threatening ischemia (CLTI) patients, and frailty and nutritional status appear to represent pivotal factor affecting prognosis among CLTI patients. The purpose of this study was to examine clinical factors (including frailty and nutritional status) relevant to WIfI clinical stage.

Methods

This retrospective study investigated 200 consecutive CLTI patients. We individually assessed WIfI clinical stage, frailty according to the Clinical Frailty Scale (CFS) score, and malnutrition according to Geriatric Nutritional Risk Index (GNRI). We then compared mortality after endovascular intervention between a WIfI stage 1, 2 group and a stage 3, 4 group, and investigated associations between baseline characteristics (including CFS and GNRI) and WIfI clinical stage.

Results

Among 200 patients, 123 patients (62%) showed WIfI stage 1 or 2, and the remaining 77 patients (38%) had WIfI stage 3 or 4. CFS score was significantly higher in the WIfI stage 3, 4 group [median 6.0, interquartile range (IQR) 5.5–7.0] compared with the WIfI stage 1, 2 group (median 5.0, IQR 4.0–6.0, p < 0.001), and GNRI was significantly lower in the WIfI stage 3, 4 group (median 88, IQR 80–97) than in the WIfI stage 1, 2 (median 103, IQR 94–111, p < 0.001). Forty patients (20%) died after endovascular intervention. Incidences of all-cause and cardiac deaths were higher in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (27% vs. 15%, p = 0.047 and 12% vs. 3%, p = 0.040, respectively). Kaplan–Meier analysis showed a significantly lower survival rate in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (p = 0.002 by log-rank test). Multivariate logistic regression analysis using relevant factors from univariate analysis showed CFS score [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.41–3.13, p < 0.001), diabetes mellitus (OR 3.17, 95%CI 1.17–8.61, p = 0.023) and GNRI (OR 0.93, 95%CI 0.89–0.97, p = 0.002) significantly associated with WIfI stage 3 or 4. In addition, multivariate ordinal logistic regression analysis for WIfI clinical stage showed CFS score (OR 1.43, 95%CI 1.09–1.89, p = 0.011), diabetes mellitus (OR 1.77, 95%CI 1.26–2.54, p < 0.001), and high-sensitivity C-reactive protein (OR 1.14, 95%CI 1.02–1.28, p = 0.041) were positively associated with WIfI clinical stage, and GNRI correlated negatively with WIfI clinical stage (OR 0.95, 95%CI 0.91–0.97, p < 0.001).

Conclusions

These results indicate that CLTI patients with high WIfI clinical stage may be more frail and malnourished, and be associated with poor prognosis after endovascular intervention.

Keywords

Chronic limb-threatening ischemia Wound,Ischemia,and foot Infection clinical stage frailty malnutrition

Introduction

Chronic limb-threatening ischemia (CLTI) represents the end-stage manifestation of peripheral artery disease.¹ A recent meta-analysis found that among untreated CLTI patients, all-cause mortality was 22% during a median follow-up of 12 months² In addition, even if CLTI patients undergo revascularization, they still exhibit poor prognosis with a high mortality rate due to cardiovascular and infectious diseases.^3,4 Recently, the Society for Vascular Surgery established the Wound, Ischemia, and foot Infection (WIfI) classification system, focusing on disease severity rather than arterial lesion characteristics.⁵ The WIfI classification, which is stratified into four clinical stages, is originally based on assessment of the 1-year risk of amputation in CLTI patients.⁵ Recent studies have shown that higher WIfI clinical stages involved a high all-cause death rate.^6,7 Thus, WIfI clinical stage has been thought to have a prognostic value in CLTI patients.

Based on the accumulated evidence, frailty and nutritional status are recognized as important factors that affect the prognosis of patients with cardiovascular disease.^8,9 Recent studies have demonstrated that frailty as assessed by the Clinical Frailty Scale (CFS)¹⁰ and malnutrition as assessed by Geriatric Nutritional Risk Index (GNRI)¹¹ were independently associated with overall survival rate among patients with CLTI.^12,13 Therefore, as with WIfI clinical stage, frailty and malnutrition appear to represent pivotal factors affecting the prognosis of CLTI patients. However, few reports have addressed associations between WIfI clinical stage and frailty or malnutrition. The current study examined clinical factors (including frailty and malnutrition) relevant to WIfI clinical stage and investigated mortality of CLTI patients undergoing endovascular intervention based on WIfI clinical stage.

Methods

Patient population

This study was a retrospective cohort study at a single center, investigating 211 consecutive CLTI patients who underwent revascularization for peripheral artery disease by endovascular intervention between February 2015 and March 2019. CLTI was diagnosed according to European Society of Cardiology guidelines.¹⁴ All patients underwent endovascular intervention using a standard technique with or without stenting, and successful endovascular intervention was defined as the establishment of at least one straight-line flow to the foot. Patients were followed-up at our hospital or by their physician. However, 11 patients were lost to follow-up. The final number of patients recruited to the study was thus 200. This study was approved by the Research and Ethics Committee of Kagoshima University Hospital and was carried out in accordance with the ethical principles stated in the 1975 Declaration of Helsinki. All patients provided written informed consent.

Measurements

Laboratory values were obtained at the time of admission before revascularization for CLTI. Levels of serum albumin, high-sensitivity C-reactive protein (hs-CRP), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, and hemoglobin were measured, and the estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation with coefficients modified for Japanese patients as follows: eGFR (ml/min/1.73 m²) = 194 × serum creatinine (mg/dL)^−1.094 × age (years)^−0.287 (× 0.739 for female subjects).¹⁵ In addition, left ventricular ejection fraction (LVEF) was obtained from echocardiography.

WIfI clinical stage, clinical frailty scale, and geriatric nutritional risk index

The WIfI classification system comprises three independent risk factors: wound, ischemia, and foot infection.⁵ All three factors are individually graded on a scale from 0 (least severe) to 3 (most severe), then the three subscores are combined into a clinical risk score, ranging from stage 1 to stage 4 (1, very low risk; 2, low risk; 3, moderate risk; and 4, high risk) at the time of admission, as previously described.⁵ Clinical frailty was also assessed at the time of admission by physicians according to the CFS derived from the Canadian Study of Health and Aging, ranging from 1 (very fit) to 9 (terminally ill).¹⁰ Furthermore, we assessed nutritional status using the GNRI, calculated using the following equation: GNRI = 14.89 × serum albumin (g/dL) + 41.7 × (body weight/ideal body weight).¹¹ Body weight/ideal body weight was set to 1 when the body weight of the patient exceeded the ideal body weight. Ideal body weight was calculated based on a body mass index of 22 kg/m². Body mass index was calculated as body weight in kilograms divided by height in meters squared.

Clinical outcomes

Clinical outcomes were retrospectively collected during follow-up. All-cause death was defined as any death after endovascular intervention. Cardiac death was defined as any death due to proximate cardiac death (myocardial infarction, heart failure, and fatal arrhythmia), and non-cardiac death was defined as any death not covered by the above definition.

The mortality after endovascular intervention was compared between a WIfI stage 1, 2 group (very low or low risk patients) and a WIfI stage 3, 4 group (moderate or high risk patients), and we then investigated the association between WIfI clinical stage and baseline characteristics, including CFS and GNRI.

Statistical analysis

Quantitative data are presented as mean ± standard deviation or median and interquartile range (IQR). Fisher’s exact test was used to compare the incidence of categorical variables, which were expressed as frequency and percentage. Continuous variables were compared between the WIfI stage 1, 2 group and the WIfI stage 3, 4 group using Student’s t-test (for values showing a normal distribution) or Mann–Whitney U test (for values showing a non-normal distribution). Cumulative survival rates for patients were estimated using a Kaplan–Meier curve evaluated by log-rank testing. Logistic regression analysis was used to analyze factors associated with WIfI stage 3 or 4, reporting odds ratios (ORs) and 95% confidence intervals (CIs). Furthermore, ordinal logistic regression analysis was also performed to analyze factors associated with WIfI clinical stage because WIfI clinical stage is an ordinal scale. Variables showing values of p < 0.05 on univariate analysis were entered into multivariate analysis. Values of p < 0.05 were considered to indicate statistical significance. Statistical analyses were performed using SAS software (JMP version 14.0).

Results

Baseline characteristics

The baseline characteristics of patients are shown in Table 1. Median age was 73 years (IQR, 64–81 years), and 118 patients (59%) were male. Notable comorbidities included hypertension (88%), diabetes mellitus (70%), dyslipidemia (66%) and hemodialysis (43%). There were 123 patients (62%) with WIfI clinical stage 1 (62 patients) or 2 (61 patients), while 77 patients (38%) had WIfI clinical stage 3 (29 patients) or 4 (48 patients). CFS score was higher in the WIfI stage 3, 4 group (median 6.0, IQR 5.5–7.0) compare with the WIfI stage 1, 2 group (median 5.0, IQR 4.0–6.0, p < 0.001) (Table 1). The WIfI stage 3, 4 group had a larger population of patients with diabetes mellitus and prior smoking compared with the WIfI stage 1, 2 group (82% vs. 62%, p = 0.003 and 60% vs. 76%, p = 0.027, respectively). Body mass index, serum albumin level, and GNRI were significantly lower in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (21.4 ± 2.8 kg/m² vs. 23.2±3.4 kg/m², p < 0.001, median 3.3 g/dL, IQR 2.9–3.7 g/dL vs. median 3.9 g/dL, IQR 3.6–4.3 g/dL, p < 0.001, and median 88, IQR 80–97 vs. median 103, IQR 94–111, p < 0.001, respectively). The concentration of hs-CRP was higher in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (median 1.59 mg/dL, IQR 0.45–5.51 mg/dL vs. median 0.20 mg/dL, IQR 0.08–059 mg/dL, p < 0.001). Table 2 shows wound, ischemia, and foot infection grades in both groups. Rates of grade 2 or 3 wound and foot infections were higher in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (Table 2).

Table 1.

Baseline patient characteristics.

Variables	Overall	Stage 1, 2 group	Stage 3, 4 group	p Value
Variables	(n = 200)	(n = 123)	(n = 77)	p Value
Age, y	73 (64–81)	70 (63–79)	75 (68–82)	0.004
Sex: Male, n (%)	118 (59)	72 (59)	46 (60)	0.88
Body mass index, kg/m²	22.5 ± 3.4	23.2 ± 3.4	21.4 ± 2.8	<0.001
CFS score	5.0 (4.0–7.0)	5.0 (4.0–6.0)	6.0 (5.5–7.0)	<0.001
Comorbidities, n (%)
Hypertension	176 (88)	111 (90)	65 (84)	0.26
Diabetes mellitus	139 (70)	76 (62)	63 (82)	0.003
Dyslipidemia	132 (66)	87 (71)	45 (58)	0.092
Current smoking	26 (13)	17 (14)	9 (12)	0.83
Prior smoking	139 (70)	93 (76)	46 (60)	0.027
Hemodialysis	86 (43)	46 (37)	40 (52)	0.056
Prior stroke	26 (13)	20 (16)	6 (8)	0.089
Prior heart failure	13 (7)	6 (5)	7 (9)	0.25
Prior myocardial infarction	32 (16)	17 (14)	15 (19)	0.32
Prior CABG	36 (18)	24 (19)	12 (16)	0.57
Medications, n (%)
Aspirin	119 (60)	77 (63)	42 (55)	0.30
Clopidogrel	94 (47)	62 (50)	32 (42)	0.25
Oral anticoagulation	66 (33)	42 (34)	24 (31)	0.76
Calcium-channel blocker	102 (51)	68 (55)	34 (44)	0.147
ACEI	10 (5)	9 (7)	1 (1)	0.092
ARB	87 (44)	59 (48)	28 (36)	0.143
β-blocker	57 (29)	40 (33)	17 (22)	0.147
Statin	109 (55)	74 (60)	35 (45)	0.058
Laboratory data
Hemoglobin, g/dL	11.7 ± 2.1	12.3 ± 1.9	11.2 ± 2.1	<0.001
hs-CRP, mg/dL	0.41 (0.11, 1.62)	0.20 (0.08, 0.59)	1.59 (0.45, 5.51)	<0.001
LDL-C, mg/dL	86 (71, 112)	90 (71, 114)	80 (64, 105)	0.041
HDL-C, mg/dL	47 (39, 57)	49 (42, 60)	44 (37, 56)	0.007
Albumin, g/dL	3.7 (3.3, 4.1)	3.9 (3.6, 4.3)	3.3 (2.9, 3.7)	<0.001
eGFR, mL/min/1.73 m²	28.5 (7.3, 58.3)	40.9 (7.6, 59.3)	10.6 (7.2, 53.6)	0.146
GNRI	97 (87, 106)	103 (94, 111)	88 (80, 97)	<0.001
LVEF, %	64.3 (53.8, 72.1)	65.3 (56.4, 73.6)	61.0 (46.3, 68.8)	0.049

Values represent mean ± standard deviation or median (interquartile range).

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass grafting; CFS, clinical Frailty Scale; eGFR, estimated glomerular filtration rate; GNRI, Geriatric Nutritional Risk Index; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LVEF, left ventricular ejection fraction; LDL-C, low-density lipoprotein cholesterol.

Table 2.

Wound, ischemia, and foot infection grades in both groups.

Category	Stage 1, 2 group	Stage 3, 4 group	p Value
Category	(n = 123)	(n = 77)	p Value
Wound, n (%)
Grade 0	86 (70)	0 (0)	<0.001
Grade 1	31 (25)	19 (25)	1.00
Grade 2	6 (5)	43 (56)	<0.001
Grade 3	0 (0)	15 (19)	<0.001
Ischemia, n (%)
Grade 0	29 (24)	7 (9)	0.013
Grade 1	48 (39)	15 (19)	0.005
Grade 2	29 (24)	23 (30)	0.33
Grade 3	17 (14)	32 (42)	<0.001
Foot infection, n (%)
Grade 0	109 (89)	18 (23)	<0.001
Grade 1	12 (10)	30 (39)	<0.001
Grade 2	2 (2)	21 (27)	<0.001
Grade 3	0 (0)	8 (10)	<0.001

Mortality after endovascular intervention

Median duration of follow-up was 966 days (IQR, 540–1268 days). Forty patients (20%) died after endovascular intervention. Thirteen cardiac deaths (heart failure, 8 patients; acute myocardial infarction, 3 patients; ventricular tachycardia, 2 patients) and 27 non-cardiac deaths (pneumonia, 15 patients; sepsis, 6 patients; others, 6 patients) were identified. Incidences of all-cause and cardiac deaths were significantly higher in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (27% vs. 15%, p = 0.047, and 12% vs. 3%, p = 0.040, respectively), and incidence of non-cardiac death did not differ between the WIfI stage 1, 2 and 3, 4 groups (12% vs. 16%, p = 0.53) (Table 3). Kaplan–Meier analysis showed a significantly lower survival rate in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (p = 0.002 by log-rank test) (Figure 1).

Table 3.

Cumulative death after endovascular intervention.

	Overall	Stage 1, 2 group	Stage 3, 4 group	p Value
	(n=200)	(n=123)	(n=77)	p Value
All-cause death, n (%)	40 (20)	19 (15)	21 (27)	0.047
Cardiac death, n (%)	13 (7)	4 (3)	9 (12)	0.040
Non-cardiac death, n (%)	27 (14)	15 (12)	12 (16)	0.53

Figure 1.

Kaplan-Meier analysis for survival rate after endovascular intervention.

Association of baseline systemic factors with WIfI clinical stage

Logistic regression analysis was performed to investigate associations between baseline characteristics and WIfI clinical stage 3 or 4. In univariate analysis, age, body mass index, CFS score, diabetes mellitus, prior smoking, hemodialysis, statin use, hemoglobin, hs-CRP, LDL-C, HDL-C, albumin, GNRI, and LVEF were significantly associated with WIfI stage 3 or 4 (Table 4). Body mass index and albumin were used to calculate GNRI. As a result, these factors were not incorporated into the multivariate analysis. Multivariate analysis showed CFS score (OR 2.06, 95%CI 1.41–3.13, p < 0.001) and diabetes mellitus (OR 3.17, 95%CI 1.17–8.61, p = 0.023) correlated positively with WIfI stage 3 or 4, and GNRI was negatively associated with WIfI stage 3 or 4 (OR 0.93, 95%CI 0.89–0.97, p = 0.002) (Table 4). We also demonstrated ordinal logistic regression analysis for WIfI clinical stage. In univariate analysis, age, body mass index, CFS score, diabetes mellitus, dyslipidemia, current smoking, hemodialysis, statin use, hemoglobin, hs-CRP, HDL-C, albumin, GNRI, and LVEF were all significantly associated with WIfI clinical stage (Table 5). In the same manner, multivariate analysis showed that CFS score (OR 1.43, 95%CI 1.09–1.89, p = 0.011), diabetes mellitus (OR 1.77, 95%CI 1.26–2.54, p < 0.001) and hs-CRP (OR 1.14, 95%CI 1.02–1.28, p = 0.041) were positively correlated with WIfI clinical stage, and GNRI was negatively associated with WIfI clinical stage (OR 0.95, 95%CI 0.91–0.97, p < 0.001) (Table 5).

Table 4.

Logistic regression analysis for WIfI clinical stage 3 or 4.

Variables	Univariate analysis			Multivariate analysis
Variables	OR	95%CI	p Value	OR	95%CI	p Value
Age	1.05	(1.02–1.08)	0.001	1.01	(0.97–1.07)	0.47
Sex, male	0.95	(0.53–1.70)	0.87
Body mass index	0.84	(0.76–0.92)	<0.001
CFS score	2.61	(1.95–3.50)	<0.001	2.06	(1.41–3.13)	<0.001
Hypertension	0.59	(0.25–1.39)	0.223
Diabetes mellitus	2.78	(1.40–5.51)	0.003	3.17	(1.17–8.61)	0.023
Dyslipidemia	0.58	(0.32–1.06)	0.075
Current smoking	1.12	(0.52–2.99)	0.66
Prior smoking	2.89	(1.13–3.88)	0.019	1.14	(0.41–3.12)	0.79
Hemodialysis	1.81	(1.01–3.22)	0.044	1.50	(0.61–3.66)	0.38
Prior stroke	0.43	(0.17–1.13)	0.089
Prior heart failure	1.95	(0.63–6.04)	0.25
Prior myocardial infarction	1.51	(0.70–3.23)	0.29
Prior CABG	0.76	(0.34–1.60)	0.48
Aspirin	0.73	(0.40–1.30)	0.28
Clopidogrel	0.69	(0.39–1.24)	0.22
Oral anticoagulation	0.87	(0.47–1.60)	0.66
Calcium-channel blocker	0.64	(0.36–1.13)	0.126
ACEI	0.17	(0.02–1.34)	0.092
ARB	0.62	(0.34–1.11)	0.108
β-blocker	0.58	(0.30–1.13)	0.113
Statin	0.55	(0.31–0.98)	0.043	0.55	(0.21–1.38)	0.20
Hemoglobin	0.75	(0.63–0.87)	<0.001	1.16	(0.90–1.51)	0.25
Hs-CRP	1.49	(1.20–1.65)	<0.001	1.15	(0.99–1.40)	0.10
LDL-C	0.99	(0.98–1.00)	0.024	0.99	(0.98–1.01)	0.21
HDL-C	0.97	(0.95–1.00)	0.017	0.99	(0.96–0.98)	0.72
Albumin	0.13	(0.06–0.24)	<0.001
eGFR	0.99	(0.98–1.00)	0.097
GNRI	0.90	(0.87–0.93)	<0.001	0.93	(0.89–0.97)	0.002
LVEF	0.97	(0.95–1.00)	0.019	0.98	(0.95–1.01)	0.33

Logistic regression analysis.

CI, confidence interval; OR, odds ratio. Other abbreviations are as in Table 1.

Table 5.

Ordinal logistic regression analysis for WIfI clinical stage.

Variables	Univariate analysis			Multivariate analysis
Variables	OR	95%CI	p Value	OR	95%CI	p Value
Age	1.04	(1.02–1.06)	0.012	1.02	(0.95–1.02)	0.35
Sex, male	1.01	(0.78–1.30)	0.94
Body mass index	0.85	(0.79–0.93)	<0.001
CFS score	1.92	(1.56–2.38)	<0.001	1.43	(1.09–1.89)	0.011
Hypertension	0.82	(0.56–1.20)	0.196
Diabetes mellitus	1.56	(1.19–2.07)	0.002	1.77	(1.26–2.54)	<0.001
Dyslipidemia	0.75	(0.57–0.98)	0.035	0.80	(0.55–1.15)	0.22
Current smoking	1.42	(1.07–1.88)	0.013	1.00	(0.63–1.59)	0.97
Prior smoking	1.01	(0.70–1.45)	0.97
Hemodialysis	1.34	(1.04–1.74)	0.023	1.14	(0.83–1.57)	0.42
Prior stroke	0.77	(0.53–1.10)	0.168
Prior heart failure	1.55	(0.94–2.58)	0.095
Prior myocardial infarction	1.34	(0.96–1.88)	0.090
Prior CABG	1.06	(0.77–1.44)	0.74
Aspirin	0.90	(0.70–1.16)	0.43
Clopidogrel	0.88	(0.69–1.14)	0.35
Oral anticoagulation	0.98	(0.75–1.28)	0.88
Calcium-channel blocker	0.84	(0.65–1.07)	0.160
ACEI	0.66	(0.37–1.13)	0.170
ARB	0.84	(0.65–1.08)	0.172
β-blocker	0.92	(0.70–1.20)	0.54
Statin	0.73	(0.57–0.95)	0.017	0.87	(0.60–1.24)	0.43
Hemoglobin	0.74	(0.65–0.84)	<0.001	0.97	(0.81–1.15)	0.69
Hs-CRP	1.33	(1.20–1.52)	<0.001	1.14	(1.02–1.28)	0.041
LDL-C	0.99	(0.98–1.00)	0.054
HDL-C	0.98	(0.96–1.00)	0.011	1.01	(0.98–1.03)	0.44
Albumin	0.52	(0.41–0.70)	<0.001
eGFR	0.99	(0.98–1.00)	0.149
GNRI	0.92	(0.89–0.93)	<0.001	0.95	(0.91–0.97)	<0.001
LVEF	0.98	(0.96–0.99)	0.012	0.98	(1.00–1.01)	0.131

Ordinal logistic regression analysis. Other abbreviations are as in Tables 1 and 4.

Discussion

The current study demonstrated that CFS score, diabetes mellitus, hs-CRP and GNRI were independently associated with WIfI clinical stage, and CLTI patients with WIfI clinical stage 3 or 4 showed a high frequency of all-cause death after endovascular intervention compared to those with WIfI stage 1 or 2.

The WIfI classification was introduced by the Society for Vascular Surgery Association.⁵ Although WIfI classification was originally based on assessment of the 1-year risk of amputation in CLTI patients,⁵ various studies have investigated the association between WIfI clinical stage and mortality in patients with CLTI.^3,4,6,7,16 In those studies, inclusion criteria of subjects differed, such as non-diabetic patients¹⁶ or medical therapy without revascularization.⁷ However, the results consistently indicated a similar tendency, in that patients with high WIfI stage showed high mortality compared to those with low WIfI stage. The main causes of death in CLTI patients are cardiovascular and infectious disease such as pneumonia and sepsis.^3,4,17 In our study, infectious disease and cardiac death were also main cause of death. In addition, the WIfI stage 3, 4 group had higher mortality after endovascular intervention compared with the WIfI stage 1, 2 group. These results are consistent with the aforementioned previous studies.

As mentioned above, WIfI clinical stage was associated with all-cause and cardiac deaths. Therefore, it is pivotal to clarify the clinical features relevant to WIfI clinical stage. We performed ordinal logistic regression analysis for WIfI clinical stage, and showed that with rises in WIfI clinical stage, CFS score rises and GNRI decreases. These results indicate that CLTI patients with high WIfI clinical stage have higher risks of frailty and malnutrition. Sarcopenia is the main cause of physical frailty and is influenced by nutritional status.^18,19 Physical activity is decreased in CLTI patients with high WIfI stage due to severe wound and foot infection, and decreases in physical activity lead to reduced skeletal muscle and the risk of sarcopenia. Furthermore, lasting foot infection is more susceptible to progressive malnutrition. Consequently, CLTI patients with high WIfI stage may have a higher risk of frailty and malnutrition. Previous studies have revealed that CFS score was independently associated with 2-year overall survival in CLTI patients,¹² and that frailty as assessed by modified frailty index was associated with an increased risk of adverse cardiac events in patients with stable claudication.²⁰ Furthermore, GNRI was associated with overall survival after endovascular intervention in CLTI patients¹³ and with overall survival and cardiovascular events in patients with peripheral artery disease.²¹ Those previous studies support the results of this study that high WIfI clinical stage closely related to malnutrition and high frailty.

Diabetes mellitus and inflammation are widely known to be factors that promote atherosclerosis.^22,23 In this study, diabetes mellites and hs-CRP significantly differed between WIfI stage 1, 2 and 3, 4 groups and were independent risk factors for WIfI clinical stage in multivariate ordinal logistics regression analysis. The association between hs-CRP and WIfI clinical grade is thought to be derived from differences in wound and foot infection grades, because the frequency of grade 2 or 3 wound and foot infection is higher in patients with high WIfI stage than in those with low WIfI stage. Another possibility should be considered, however. Atherosclerosis is a widely accepted inflammatory disease²³ and CRP is associated with an increased risk of future coronary heart disease.²⁴ CLTI is the most advanced form of peripheral artery disease,¹ and CRP has been independently associated with overall survival and cardiovascular events.²¹ Furthermore, even in the general population, hs-CRP is associated with incident peripheral artery disease and CLTI.²⁵ Thus, elevated hs-CRP among patients with high WIfI stage in our study may have expressed a state of systemic atherosclerosis as a surrogate maker in addition to the severity of wound and foot infection. Diabetes mellitus is an established risk factor associated with the development of coronary artery^26,27 and peripheral artery disease.²⁸ In addition, patients with diabetes mellitus are widely recognized to be at higher risk of amputation,²⁹ and diabetes mellitus is independently associated with cardiovascular events in CLTI patients.²¹ This seems consistent with previous studies that diabetes mellitus correlates positively with WIfI clinical stage in this study.

A few limitations need to be considered for this study. First, the present study was a retrospective study, and WIfI clinical stage was assessed retrospectively using pretreatment photographs taken from multiple angles in some patients. Second, this study contained a relatively small number of patients, and the mortality rate after endovascular intervention was lower than that in the previous studies. We thus compared mortality between two groups (WIfI stage 1, 2 group and WIfI stage 3, 4 group). Third, while we were able to demonstrate a correlation between WIfI clinical stage and CFS score, the CFS is a semiquantitative scale of frailty, and we were unable to investigate the relationship between mortality and other frailty factors such as muscular strength.

Conclusion

The current study demonstrated that WIfI clinical stage correlated independently with CFS score and GNRI, and CLTI patients with WIfI clinical stage 3 or 4 had a high mortality after endovascular intervention compared to those with WIfI stage 1 or 2. This study suggests that CLTI patients with high WIfI clinical stage may be more frail and malnourished, and be associated with poor prognosis after endovascular intervention.

Footnotes

Acknowledgments

We thank the staff of the Department of Cardiovascular Medicine and Hypertension at the Graduate School of Medical and Dental Sciences, Kagoshima University for their assistance with data processing.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the Japan Society for the Promotion of Science KAKENHI (grant no. 16H070890).

ORCID iD

Daisuke Kanda

References

Conte

Bradbury

Kolh

GVG Writing Group , et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019; 69: 3S–e40.

Abu Dabrh

Steffen

Undavalli

, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg 2015; 62: 1642–1651.

Azuma

Takahara

Kodama

, et al. Predictive model for mortality risk including the wound, ischemia, foot infection classification in patients undergoing revascularization for critical limb ischemia. Circ Cardiovasc Interv 2019; 12(12): e008015.

Hata

Iida

Asai

, et al. Risk stratification for 2-Year mortality in patients with chronic limb-threatening ischemia undergoing endovascular therapy. J Atheroscler Thromb 2021; 28: 477–482.

Mills

Sr Conte

Armstrong

, et al. The society for vascular surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg 2014; 59: 220–234.

Darling

McCallum

Soden

, et al. Predictive ability of the society for vascular surgery wound, ischemia, and foot infection (WIfI) classification system after first-time lower extremity revascularizations. J Vasc Surg 2017; 65: 695–704.

van Haelst

STW

Teraa

Moll

, et al. Prognostic value of the society for vascular surgery wound, Ischemia, and foot infection (WIfI) classification in patients with no-option chronic limb-threatening ischemia. J Vasc Surg 2018; 68: 1104–1113.

Veronese

Cereda

Stubbs

, et al. Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis. Ageing Res Rev 2017; 35: 63–73.

Minamisawa

Miura

Motoki

, et al. Geriatric nutritional risk index predicts cardiovascular events in patients at risk for heart failure. Circ J 2018; 82: 1614–1622.

10.

Rockwood

Song

MacKnight

, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173: 489–495.

11.

Bouillanne

Morineau

Dupont

, et al. Geriatric nutritional risk index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr 2005; 82: 777–783.

12.

Takeji

Yamaji

Tomoi

, et al. Impact of frailty on clinical outcomes in patients with critical limb ischemia. Circ Cardiovasc Interv 2018; 11(7): e006778.

13.

Shiraki

Iida

Takahara

, et al. The geriatric nutritional risk index is independently associated with prognosis in patients with critical limb ischemia following endovascular therapy. Eur J Vasc Endovasc Surg 2016; 52: 218–224.

14.

Aboyans

Ricco

Bartelink

MEL

, et al. ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. endorsed by: the european stroke organization (ESO). The task force for the diagnosis and treatment of peripheral arterial diseases of the European society of cardiology (ESC) and of the European society for vascular surgery (ESVS). Eur Heart J 2018; 39: 763–816.

15.

Matsuo

Imai

Horio

, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney 2009; 53: 982–992.

16.

Beropoulis

Stavroulakis

Schwindt

, et al. Validation of the wound, Ischemia, foot Infection (WIfI) classification system in nondiabetic patients treated by endovascular means for critical limb ischemia. J Vasc Surg 2016; 64: 95–103.

17.

Soga

Iida

Takahara

, et al. Two-year life expectancy in patients with critical limb ischemia. JACC Cardiovasc Interv 2014; 7: 1444–1449.

18.

Sze

Zhang

Pellicori

, et al. Prognostic value of simple frailty and malnutrition screening tools in patients with acute heart failure due to left ventricular systolic dysfunction. Clin Res Cardiol 2017; 106: 533–541.

19.

Houston

Nicklas

Ding

, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and body composition (Health ABC) study. Am J Clin Nutr 2008; 87: 150–155.

20.

Schaller

Ramirez

Gasper

, et al. Frailty is associated with an increased risk of major adverse cardiac events in patients with stable claudication. Ann Vasc Surg 2018; 50: 38–45.

21.

Matsuo

Kumakura

Kanai

, et al. The geriatric nutritional risk index predicts longtTerm survival and cardiovascular or limb events in peripheral arterial disease. J Atheroscler Thromb 2020; 27: 134–143.

22.

Malmberg

Yusuf

Gerstein

, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000; 102: 1014–1019.

23.

Ross

. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115–126.

24.

Cushman

Arnold

Psaty

, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005; 112: 25–31.

25.

Ding

Yang

Ballew

, et al. Fibrosis and inflammatory markers and long-term risk of peripheral artery disease: The ARIC study. Arterioscler Thromb Vasc Biol 2020; 40: 2322–2331.

26.

Stratton

Adler

Neil

, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–412.

27.

Blake

Meigs

Muller

, et al. Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors: results from the Baltimore Longitudinal Study on Aging. Diabetes 2004; 53: 2095–2100.

28.

Song

Rudan

Zhu

, et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 2019; 7: e1020–1030.

29.

Moss

Klein

. The 14-year incidence of lower-extremity amputations in a diabetic population. The wisconsin epidemiologic study of diabetic retinopathy. Diabetes Care 1999; 22: 951–959.