Abstract
Background: Clinical impact of inframalleolar (IM) angioplasty in patients with chronic limb-threatening ischemia (CLTI) is still controversial.
Methods and Results: This single-center, retrospective study included 168 patients with CLTI and tissue loss who underwent angioplasty for IM lesions. Angiographic follow up was performed at reintervention between April 2010 and December 2020. The outcome measure was the incidence of angiographic deterioration characterized by severe restenosis or occlusion of mildly stenotic lesions, occlusion of severely stenotic lesions, or extension of the occlusion length at reintervention. Angiographic deterioration was observed in 47.7% of patients, with the majority attributed to occlusion in severely stenotic lesions. Multivariate analysis revealed that a distal reference vessel diameter ≤1.0 mm in the initial angioplasty (hazard ratio 1.91 [95% confidence interval 1.20–3.04]; P=0.006) was significantly associated with angiographic deterioration of IM lesions at reintervention.
Conclusions: Angiographic deterioration occurred in approximately half of the patients with CLTI who underwent IM angioplasty and reintervention.
Chronic limb-threatening ischemia (CLTI) is the most severe manifestation of lower extremity artery disease, which is characterized by ischemic rest pain and ulceration or gangrene, and is associated with a high risk of major amputation.1
Over 70% of patients with CLTI have inframalleolar (IM) lesions,2,3 and the severity of IM lesions was reported to have an impact on clinical outcomes.3,4 Although global vascular guidelines1 suggest a novel classification for IM lesions as a Global Limb Anatomic Staging System (GLASS) IM/pedal descriptor, the clinical impact of IM angioplasty in patients with CLTI remains controversial. In addition, the angiographic changes before and after IM angioplasty have not been systematically studied.
In this study, we aimed to investigate the details of angiographic changes in IM lesions and explore the predictive factors in patients with CLTI accompanied by tissue loss who underwent endovascular therapy (EVT) for IM lesions and follow-up angiography at reintervention.
Methods
Study Participants
This retrospective study used a clinical database consisting of 1,712 patients with CLTI and tissue loss who underwent EVT between April 2010 and December 2020 at a single cardiovascular center. We excluded 1,347 patients treated only for above-ankle lesions. Of the remaining 365 patients who underwent EVT for IM lesions, 168 patients who underwent reintervention during the follow-up period were included in the present study. This study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the ethics committee of Kansai Rosai Hospital. As this was an observational study that did not use human biological specimens and was without intervention, the requirement for written informed consent was waived following the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Instead, relevant information regarding the study was open to the public, and opportunities to refuse participation were provided.
Baseline Assessment and Revascularization Strategy
The severity of limb ischemia in the index limb was routinely evaluated using the ankle-brachial index and skin perfusion pressure. The severity and location of the lower limb arterial lesions were evaluated using duplex ultrasonography. Hemodynamically significant arterial lesions were diagnosed using digital subtraction angiography before EVT. In this study, the revascularization strategy for IM lesions was not prespecified and depended on the operator’s discretion. Generally, we performed EVT for infrapopliteal and IM lesions using the ipsilateral antegrade approach to obtain 1 straight blood flow to the wound. If wire crossing using the antegrade approach failed, we switched to the bidirectional approach using a tibial puncture, trans-collateral, or trans-pedal route. After successful wire crossing, the lesions were treated using plain angioplasty. The main target vessels for IM lesions were the dorsalis pedis, lateral plantar, medial plantar, or pedal arch, depending on the distribution of the wound and the operator’s discretion. Reintervention was conducted for delayed healing or worsening of wound conditions accompanied by decreased arterial flow in infrapopliteal lesions. Drug-coated balloons, bare metal stents, drug-eluting stents, and atherectomy devices were not used for IM lesions because they were not approved for use in Japan during the study period.
Definitions
CLTI was classified according to global vascular guidelines.1 The GLASS1 was assessed using high-quality digital subtraction angiography before revascularization. Disease below the arch was classified using the small artery disease (SAD)2 score, defined as follows: SAD 0, no or mild stenosis; SAD 1, significant stenosis; and SAD 2, occlusion of at least 1 lesion in the pedal arch, metatarsal, digital, or calcaneal arteries (Figure 1). Major amputation was defined as an amputation above the ankle. Complete wound healing was defined as complete epithelialization of all wounds without death or major amputation. The date of wound healing was defined as the date when complete wound epithelialization was observed.
Study Outcome Measures
The main outcome measure was the frequency of angiographic deterioration of IM lesions, defined as severe restenosis or occlusion of mildly stenotic lesions, occlusion of severely stenotic lesions, or extension of occlusion length at reintervention. We also explored predictors of angiographic deterioration in IM lesions and their impact on amputation-free survival. The frequency and predictors of SAD progression, defined as an increase in SAD score ≥1 at reintervention, were also investigated.
Statistical Analysis
Data are presented as means±standard deviations and percentages for continuous and discrete variables, unless otherwise specified. The association between angiographic deterioration and anatomical characteristics was evaluated using a Cox regression hazards model with hazard ratios (HRs) and 95% confidence intervals (CIs). Independent associations were explored using a multivariable model in which anatomic characteristics with statistical significance in univariate analysis, as well as age, body mass index, ambulatory status, diabetes, hemodialysis, and Wound, Ischemia, foot Infection (WIfI)5 clinical stages were entered as explanatory variables. Amputation-free survival rates were estimated using the Kaplan-Meier method, and differences between groups were evaluated using the log-rank test when necessary. Time-dependent Cox regression analysis was used for time-dependent covariates. Statistical significance was set at P<0.05. Statistical analyses were performed using SPSS (version 24.0; SPSS Inc., Chicago, IL, USA) and R (version 4.2.2; The R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline Characteristics
Table 1 summarizes the patient, limb, and lesion characteristics. Specifically, 67.9% of the patients were male, and the mean age was 70±9 years. The prevalence of diabetes and hemodialysis was 68.9% and 70.8%, respectively. Moreover, 47.6% of the patients were classified as clinical stage 4 according to the WIfI classification. Using the GLASS classification, 8.9% and 60.1% of patients were classified as grade 4 in the femoropopliteal and infrapopliteal territories, respectively. GLASS IM/pedal descriptor P2 and SAD 2 accounted for 26.2% and 37.5%, respectively. There were no statistically significant differences in baseline characteristics between patients with angiographic deterioration and those without.
Table 1.
Baseline Characteristics
| |
All |
Angiographic
deterioration (+) |
Angiographic
deterioration (−) |
P value |
| No. patients |
168 |
80 |
88 |
|
| Patient characteristics |
| Male |
114 (67.9) |
52 (65.0) |
62 (70.5) |
0.51 |
| Age (years) |
70±9 |
71±8 |
69±10 |
0.13 |
| BMI (kg/m2) |
22.0±3.9 |
22.0±3.7 |
22.1±4.1 |
0.82 |
| Non-ambulatory status |
61 (36.3) |
32 (40.0) |
29 (33.0) |
0.42 |
| Diabetes |
115 (68.9) |
55 (68.8) |
60 (69.0) |
1.00 |
| Hemodialysis |
119 (70.8) |
62 (77.5) |
57 (64.8) |
0.09 |
| Coronary artery disease |
79 (47.3) |
40 (50.6) |
39 (44.3) |
0.44 |
| Cerebrovascular disease |
23 (13.8) |
13 (16.5) |
10 (11.4) |
0.38 |
| Congestive heart failure |
15 (12.7) |
10 (18.2) |
5 (7.9) |
0.11 |
| LVEF (%) |
60±13 |
59±15 |
60±12 |
0.44 |
| Serum albumin (g/dL) |
3.3±0.6 |
3.4±0.6 |
3.3±0.6 |
0.29 |
| Medical therapy |
| Antiplatelet agent |
130 (77.4) |
72 (90.0) |
78 (88.6) |
0.81 |
| Anticoagulant |
38 (22.6) |
18 (22.5) |
22 (25.0) |
0.72 |
| Statins |
130 (77.4) |
28 (35.0) |
22 (25.0) |
0.18 |
| Oral hypoglycemic agent |
38 (22.6) |
22 (27.5) |
30 (34.1) |
0.41 |
| Insulin |
130 (77.4) |
24 (30.0) |
37 (42.0) |
0.11 |
| Limb characteristics |
| Ankle-brachial index |
0.70±0.17 |
0.69±0.17 |
0.70±0.18 |
0.79 |
| Skin perfusion pressure (mmHg) |
24±12 |
25±12 |
23±12 |
0.34 |
| Rutherford classification |
|
|
|
0.096 |
| 5 (minor tissue loss) |
130 (77.4) |
57 (71.2) |
73 (83.0) |
|
| 6 (major tissue loss) |
38 (22.6) |
23 (28.7) |
15 (17.0) |
|
| Clinical stages in WIfI classification |
|
|
|
0.50 |
| 1 (Very low risk) |
11 (6.5) |
4 (5.0) |
7 (8.0) |
|
| 2 (Low risk) |
19 (11.3) |
10 (12.5) |
9 (10.2) |
|
| 3 (Moderate risk) |
58 (34.5) |
32 (40.0) |
28 (31.7) |
|
| 4 (High risk) |
80 (47.6) |
34 (42.5) |
44 (50.0) |
|
| Arterial lesion characteristics |
| GLASS femoropopliteal |
|
|
|
0.46 |
| Grade 0 |
109 (64.9) |
56 (70.0) |
53 (60.2) |
|
| Grade 1 |
17 (10.1) |
7 (8.8) |
10 (11.4) |
|
| Grade 2 |
18 (10.7) |
9 (11.2) |
9 (10.2) |
|
| Grade 3 |
9 (5.4) |
4 (5.0) |
5 (5.7) |
|
| Grade 4 |
15 (8.9) |
4 (5.0) |
11 (12.5) |
|
| GLASS infrapopliteal |
|
|
|
0.21 |
| Grade 0 |
8 (4.8) |
1 (1.2) |
7 (8.0) |
|
| Grade 1 |
10 (6.0) |
6 (7.5) |
4 (4.5) |
|
| Grade 2 |
16 (9.5) |
6 (7.5) |
10 (11.4) |
|
| Grade 3 |
33 (19.6) |
15 (18.8) |
18 (20.5) |
|
| Grade 4 |
101 (60.1) |
52 (65.0) |
49 (55.7) |
|
| GLASS stage |
|
|
|
0.057 |
| Stage I |
28 (16.7) |
12 (15.0) |
16 (18.2) |
|
| Stage II |
44 (26.2) |
15 (18.8) |
29 (33.0) |
|
| Stage III |
96 (57.1) |
53 (66.2) |
43 (48.9) |
|
| GLASS inframalleolar/pedal descriptor |
|
|
|
0.064 |
| Grade P0 |
47 (28.0) |
29 (36.2) |
18 (20.5) |
|
| Grade P1 |
77 (45.8) |
34 (42.5) |
43 (48.9) |
|
| Grade P2 |
44 (26.2) |
17 (21.2) |
27 (30.7) |
|
| SAD score |
|
|
|
0.27 |
| SAD 0 |
32 (19.0) |
13 (16.2) |
19 (21.6) |
|
| SAD 1 |
73 (43.5) |
40 (50.0) |
33 (37.5) |
|
| SAD 2 |
63 (37.5) |
27 (33.8) |
36 (40.9) |
|
Data are presented as n (%) or mean±standard deviation. BMI, body mass index; GLASS, Global Limb Anatomic Staging System; LVEF, left ventricular ejection fraction; SAD, small artery disease; WIfI, wound, ischemia, and foot infection.
Frequency of Angiographic Deterioration at Reintervention
Angiographic deterioration was observed in 47.7% (n=80) of patients (Figure 2). Among the cases with angiographic deterioration, occlusion of severely stenotic lesions, severe restenosis or occlusion of mildly stenotic lesions, and extension of occlusion length accounted for 50.0%, 37.5%, and 12.5% of cases, respectively. Representative cases of angiographic deterioration are shown in Figure 3.
Association Between Baseline Characteristics and Angiographic Deterioration
As shown in Table 2, the univariable analysis revealed that a distal reference vessel with diameter ≤1.0 mm in the initial angioplasty was a significant predictor of angiographic deterioration of IM lesions at reintervention. The multivariable analysis confirmed an independent association for a distal reference vessel diameter ≤1.0 mm in the initial angioplasty (HR 1.91 [95% CI 1.20–3.04]; P=0.006).
Table 2.
Association Between Angiographic Characteristics and Angiographic Deterioration of Inframalleolar Lesions at Reintervention
| |
Univariate model |
Multivariate model |
| HR (95% CI) |
P value |
HR (95% CI) |
P value |
| GLASS infrapopliteal |
1.21 (0.97–1.51) |
0.085 |
|
|
| GLASS inframalleolar/pedal descriptor |
0.81 (0.60–1.10) |
0.17 |
|
|
| SAD score |
1.25 (0.92–1.70) |
0.16 |
|
|
| Bilateral calcification in inframalleolar lesions |
1.33 (0.85–2.08) |
0.21 |
|
|
| Distal reference vessel diameter ≤1.0 mm |
1.99 (1.27–3.14) |
0.003 |
1.91 (1.20–3.04) |
0.006 |
Data are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariate model adjusted for age, BMI, ambulatory status, diabetes, hemodialysis, and WIfI clinical stage (used to predict 1-year amputation risk). Age and BMI were treated as continuous in the analysis. Abbreviations as in Table 1.
Impact of Angiographic Deterioration on Amputation-Free Survival and Wound Healing
Figure 4 shows the Kaplan-Meier curve for amputation-free survival. The 12-month amputation-free survival rate was significantly lower in patients with angiographic deterioration than in those without (77.3% vs. 85.5%; log-rank P=0.035). The multivariate time-dependent Cox regression analysis revealed that angiographic deterioration for a time-dependent covariate was significantly associated with amputation-free survival (HR 3.43 [95% CI 1.75–6.71]; P<0.001; Table 3).
Table 3.
Association Between Angiographic Deterioration and Amputation-Free Survival in Time-Dependent Cox Regression Analysis
| |
Univariate model |
Multivariate model |
| HR (95% CI) |
P value |
HR (95% CI) |
P value |
| Angiographic deterioration |
4.06 (2.12–7.79) |
<0.001 |
3.43 (1.75–6.71) |
<0.001 |
| Male |
1.42 (0.71–2.81) |
0.31 |
|
|
| Age >75 years |
1.43 (0.75–2.72) |
0.28 |
|
|
| BMI <18.5 kg/m2 |
1.34 (0.63–2.83) |
0.44 |
|
|
| Non-ambulatory status |
1.96 (1.04–3.68) |
0.036 |
1.71 (0.90–3.26) |
0.11 |
| Diabetes |
1.43 (0.70–2.94) |
0.33 |
|
|
| Hemodialysis |
2.38 (1.05–5.41) |
0.039 |
2.04 (0.89–4.69) |
0.093 |
| WIfI clinical stage 4 |
1.53 (0.82–2.85) |
0.19 |
|
|
| LVEF <50% |
1.71 (0.85–3.47) |
0.13 |
|
|
| Serum albumin <3.0 g/dL |
1.56 (0.78–3.13) |
0.21 |
|
|
Data are presented as HRs with 95% CIs. Angiographic deterioration was analysed as a time-dependent covariate. Abbreviations as in Tables 1,2.
The Supplementary Figure shows the Kaplan-Meier curve for wound healing. The 12-month wound-healing rate was not significantly different between patients with angiographic deterioration and those without (49.0% vs. 57.4%; log-rank P=0.17).
Frequency and Predictors of SAD Progression at Reintervention
Additionally, in 105 patients with SAD 0–1 in the initial procedure, SAD progression at reintervention was observed in 45 (42.9%) patients, and a distal reference vessel diameter ≤1.0 mm was significantly associated with SAD progression at reintervention (HR 4.61 [95% CI 2.30–9.25]; P<0.001) after multivariate analysis (Table 4).
Table 4.
Association Between Angiographic Characteristics and SAD Progression at Reintervention
| |
Univariate model |
Multivariate model |
| HR (95% CI) |
P value |
HR (95% CI) |
P value |
| GLASS infrapopliteal |
0.99 (0.77–1.28) |
0.96 |
|
|
| GLASS inframalleolar/pedal descriptor |
1.09 (0.76–1.57) |
0.63 |
|
|
| Bilateral calcification in inframalleolar lesions |
1.42 (0.78–2.58) |
0.25 |
|
|
| Distal reference vessel diameter ≤1.0 mm |
4.90 (2.58–9.31) |
<0.001 |
4.61 (2.30–9.25) |
<0.001 |
Data are presented as HRs with 95% CIs. Multivariate model adjusted for age, BMI, ambulatory status, diabetes, hemodialysis, and WIfI clinical stage (used to predict 1-year amputation risk). Age and BMI were treated as continuous in the analysis. Abbreviations as in Tables 1,2.
Discussion
Summary of the Present Study
The present study revealed that angiographic deterioration in IM lesions and SAD progression were observed in 47.7% and 42.9% of patients with CLTI accompanied by tissue loss who underwent IM angioplasty and follow-up angiography at reintervention, respectively. In the multivariate analysis, a distal reference vessel diameter ≤1.0 mm in the initial angioplasty was identified as an independent predictor for both angiographic deterioration in IM lesions and SAD progression. To the best of our knowledge, this is the first report of angiographic changes after IM angioplasty.
The restenosis rate after EVT in infrapopliteal lesions has been reported to be as high as 74% at 3 months, which is higher than the angiographic deterioration rate observed in our study.6 However, in infrapopliteal lesions, if the outflow arteries in IM lesions are preserved, reintervention is relatively straightforward. In contrast, when angiographic deterioration occurs in IM lesions, it often results in a ‘desert foot’ with no outflow arteries, making it difficult to achieve effective blood flow even after reintervention. The significant increase in mortality or major amputation risk observed after angiographic deterioration in our study may be influenced by this mechanism.
Controversy in Outcomes of EVT for IM Lesions and Their Causes
In the 2017 Society for Cardiovascular Angiography and Interventions guidance, appropriate use criteria for peripheral arterial interventions were updated and the negative influence of IM disease on wound-healing rates were documented.7 Although global vascular guidelines in 2019 suggested the anatomic classification system for IM lesions as a GLASS IM/pedal descriptor, the outcomes and indications of IM angioplasty remain unclear.1
Nakama et al.8 reported results from the RENDEZVOUS registry regarding EVT for IM lesions. They found a higher wound-healing rate and shorter wound-healing time in patients who underwent pedal arch intervention than in those who did not. Similarly, Jung et al.9 conducted a single-center retrospective study using propensity score matching to compare patients with CLTI who underwent pedal arch angioplasty with those who did not. They reported that the wound-healing rate was significantly higher in patients who underwent successful pedal arch angioplasty than in those who did not. These results suggest that maximizing short-term blood flow to wounds using pedal arch angioplasty may be beneficial. However, it is not rare in clinical practice to encounter cases in which stenotic IM lesions in the initial procedure become totally occluded at reintervention. Previous studies have not mentioned the details of lesion morphology at reintervention, and angiographic changes after IM angioplasty remain unknown.
A recent report has also indicated that additional intervention for IM to infrapopliteal lesions was associated with an increased risk of major amputation and major adverse limb events.10 Based on the results of this study, the angiographic deterioration in IM lesions at reintervention, accompanied by a reduction in the peripheral vascular bed, may be associated with an increased risk of these clinical events.
Mechanism of Angiographic Deterioration in IM Lesions and SAD Progression
The exact mechanisms underlying angiographic deterioration and SAD progression remain unclear. However, considering that a distal reference vessel diameter ≤1.0 mm was detected as a predictor of both phenomena, oversized balloons may lead to a larger arterial dissection by involving the ostium of small branches and occluding these branches, resulting in angiographic deterioration in IM lesions. Additionally, thrombus microemboli, dispersed plaques, and guidewire polymers during EVT may obstruct the peripheral vascular bed more distally than lesions treated with balloon angioplasty,11 resulting in SAD progression. Further investigation is required to elucidate these mechanisms.
Clinical Implications
While the effectiveness of bypass surgery over EVT has been demonstrated in the BEST-CLI study,12 it has been reported that suitability of the Japanese population in the inclusion criteria is limited.13 Therefore, an endovascular-first strategy remains mainstream for patients with CLTI, especially for frail patients. However, this study suggests that intervention for IM lesions increases the risk of deteriorating arterial lesion severity at reintervention. If IM angioplasty is performed, active intervention for wounds, such as early minor amputation, will be necessary before blood flow is diminished. In particular, for patients with small distal reference vessels, assessment of the great saphenous vein and the procedural feasibility of early bypass conversion should be considered instead of repeated EVT. In the future, further research is required to evaluate the efficacy and safety of this treatment strategy for IM lesions after consideration of the patient’s background, angiographic features, and wound severity.
Study Limitations
The present study has several limitations. First, this was a retrospective observational study that did not adopt a prospective randomized design. Second, the sample size was small. Third, patients who did not undergo reintervention were excluded. Details of the patients who did not undergo reintervention are as follows: 85 cases achieved complete wound healing; 16 cases underwent major amputations; 54 cases died with unhealed wounds; and 42 cases discontinued follow up. While angiographic changes cannot be examined in these groups of patients, the findings of this study may be helpful for cases with a high risk for reintervention, which are clinically problematic. Of course, future studies, including those who did not require reintervention, will be needed. Last, angiography was assessed by a single observer only; therefore, intra- and interobserver validation and evaluation in the core laboratory were not conducted.
Conclusions
Angiographic deterioration occurred in approximately half of the patients with CLTI who underwent IM angioplasty and reintervention. Small vessel diameter was significantly associated with angiographic deterioration.
Acknowledgments
The authors thank the medical staff at Kansai Rosai Hospital for performing the catheterization procedures and data collection. The first author expresses his gratitude to his wife for her support and encouragement.
Disclosures
The other authors declare no association with any individual, company, or organization having a vested interest in the subject matter/products mentioned in this article.
IRB Information
This study was approved by the ethics committee of Kansai Rosai Hospital (Reference no. 23D109g).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-24-0103
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