Longitudinal changes in skin perfusion pressure after endovascular therapy in patients with chronic limb-threatening ischemia

Abstract

Purpose

The skin perfusion pressure (SPP) increases after endovascular treatment (EVT) for up to 1 month, although changes beyond 1 month remain unreported. This study aimed to investigate the changes in the SPP over time after EVT.

Materials and methods

This was a single-center, prospective, observational study. We included patients with chronic limb-threatening ischemia who underwent EVT between January 2019 and July 2022. We evaluated the SPP after EVT monthly for up to 3 months and compared the changes in the SPP between patients with different comorbidities. Moreover, we investigated the independent predictors of recurrent foot ischemia using a multivariate analysis.

Results

Overall, 87 patients were included in the study. The mean preprocedural dorsal and plantar SPP was 33.9 ± 14.7 and 33.4 ± 13.1 mmHg, respectively. After the procedure, the SPP significantly increased at 1 month but decreased during months 2 and 3 (the dorsal SPP at 1, 2, and 3 months was 59.6 ± 20.3, 48.3 ± 20.9, and 39.7 ± 14.7, respectively, p < 0.01; the plantar SPP at 1, 2, and 3 months was 57.3 ± 18.2, 48.2 ± 15.6, and 40.5 ± 15.3, respectively, p < 0.01). Changes in the SPP did not differ among patients with different comorbidities. The multivariate analysis revealed that severe infrapopliteal calcification was an independent predictor of recurrent foot ischemia (odds ratio, 3.8; 95% confidence interval, 1.1–13.4; p = 0.04).

Conclusion

The SPP after EVT significantly increased at 1 month and decreased monthly for up to 3 months. Severe infrapopliteal calcification was the sole predictor of foot ischemia recurrence. Meticulous follow-up after EVT and regular hemodynamic examinations are important.

Keywords

Chronic limb-threatening ischemia endovascular therapy skin perfusion pressure infrapopliteal calcification longitudinal change

Introduction

The skin perfusion pressure (SPP), which measures microcirculation within the foot, is the gold standard for evaluating foot ischemia in patients with chronic limb-threatening ischemia (CLTI). Castronuovo et al. were the first to report the SPP as a useful diagnostic tool for patients with CLTI.¹ In addition, Watanabe et al. demonstrated that the SPP was useful for assessing improvements in tissue circulation and predicting the likelihood of wound healing.² Since then, numerous papers have demonstrated the usefulness of the SPP.^3–6

However, the timing of postprocedural SPP measurements varies among these studies, and little is known about the longitudinal changes in the SPP after revascularization. Iida et al. found that the restenosis rate after balloon angioplasty of the infrapopliteal artery was approximately 70%.⁷ A multicenter registry study reported that it took approximately 3 months to achieve complete wound healing in patients with CLTI.⁸ Thus, evaluating the longitudinal SPP changes in the first 3 months after the procedure is necessary. Recently, Ichihashi et al. reported changes in the SPP after endovascular treatment (EVT) and showed that the SPP after EVT increases for up to 1 month, although the data after 1 month are lacking.⁹ In addition, no study has assessed foot ischemic changes using the SPP after EVT.

Thus, we conducted a single-center prospective study to assess the longitudinal changes in the SPP after EVT for up to 3 months after the procedure and to explore the risk factors that affect SPP decline.

Methods

Study design and population

This prospective study included data from patients with CLTI who underwent EVT between January 2019 and July 2022 at the Nagoya Heart Center.

The inclusion criteria were as follows: (1) age ≥20 years with symptomatic lower limb ischemia, defined as Rutherford categories 5 and 6¹⁰; (2) stenotic or occlusive lesions including the infrapopliteal artery and the SPP of <40 mmHg before the procedure; and (3) successful endovascular revascularization to achieve direct blood flow to the ischemic foot. The exclusion criteria were surgical bypass or a major amputation scheduled within 30 days of EVT. In patients with bilateral disease, the leg that underwent the first successful revascularization was registered.

The primary objective was to determine the SPP changes after EVT for 3 months. Based on a power calculation, 60 patients will provide a statistical power of 80%, using an alpha of 5%. During the study period, 183 patients with CLTI underwent EVT. We excluded 44 patients who underwent repeat EVT, 21 with bilateral disease, 22 who received reintervention, and nine who were lost at follow-up and refused to participate in this study. Therefore, 87 patients (87 limbs) were included in this study (Figure 1).

Figure 1.

Patient selection flow chart.

This study was conducted in accordance with the latest version of the Declaration of Helsinki. The study design was approved by the Institutional Review Board of Nagoya Heart Center (approval no. NHC 2018-1010-04). The approval date was 10th October 2018. Written informed consent was obtained from each patient before EVT. If the patient was objectively determined to lack the ability to give informed consent, informed consent was obtained from their relative.

Outcome measures

We defined the outcomes as follows: the SPP before EVT and at 1, 2, and 3 months after EVT; and the recurrence of foot ischemia at 3 months. Recurrence of foot ischemia was defined as the SPP of <40 mmHg after EVT.

The SPP after EVT was measured after the final EVT.

The SPP was measured using a dedicated device (PAD 4000; Kaneka Medical Products, Osaka, Japan). A laser Doppler probe was placed under an 8.0 cm-wide blood pressure cuff wrapped around the middle of the first and second metatarsals on the dorsal and plantar aspects of the foot.

Follow-up

All patients were followed once or twice a week at our outpatient foot care clinic for up to 3 months after EVT. During the clinical follow-up, we did not perform reintervention. However, if the foot ischemia was urgent, we performed EVT and excluded the patient from this study.

Intervention

The operators determined the puncture site and method of endovascular recanalization according to the clinical condition and endovascular strategy. In some cases, EVT was performed in two stages. A guidewire was advanced into the culprit lesion and the lesion was dilated using an optimally sized balloon catheter or stent at the operators’ discretion. For aortoiliac lesions, we deployed a bare nitinol stent (BNS) or a stent graft as the final device. In femoropopliteal lesions, we first used an optimally sized balloon after crossing the culprit lesion and then deployed a BNS, a drug-eluting stent (DES), an interwoven stent, or a stent graft if severe dissection (Type C or higher) or recoil occurred. If the dissection was less than Type B, we completed the procedure or used a drug-coated balloon (DCB). For infrapopliteal lesions, we used an optimally sized balloon after crossing the culprit lesion; however, BNSs, DESs, and DCBs are not available for infrapopliteal lesions in Japan.

Before revascularization for infrapopliteal lesions, the location of the nonhealing ulceration/gangrene was confirmed, and the angiosome-based favorable target lesion was assessed using digital angiography. First, angiosome-based arterial recanalization was attempted; however, when treatment of the angiosome-based target lesions failed, a nonangiosome-oriented lesion via a collateral network was treated when blood flow to the wound was insufficient.¹¹

Even in the case of successful angiosome-oriented target arterial recanalization, multivessel recanalization was performed depending on the wound status and operators’ discretion.¹²

Definition

Patients with CLTI include a broader and more heterogeneous group of those with varying degrees of ischemia that may delay wound healing and increase the risk of amputation.¹³

The Global Limb Anatomical Staging System (GLASS) is defined as a staging system that stratifies the anatomical complexity of lesions in terms of revascularization.¹³

The Wound, Ischemia, and foot Infection (WIfI) grade is composed of the grade of wound extent, ischemia status, and severity of infection and is divided into four groups.¹⁴

In the current study, the criterion for intervention was a preprocedural SPP of <40 mmHg. Successful EVT was defined as the successful treatment of all hemodynamically significant stenoses or occlusions to provide inline flow to the foot.

Calcification with >50% of circumference and consisting of diffuse, bulky, or coral reef-like plaques that could probably compromise the endovascular outcome was defined as severe.

Statistical analyses

Data are presented as means ± standard deviation or medians (interquartile range, 1st, 3rd quartiles) for continuous variables and as frequencies (percentages) for categorical variables unless otherwise indicated. Statistical significance was set at p < 0.05, and 95% confidence intervals (CIs) were reported where appropriate.

The overall SPP measurements were compared using the paired t-test and ANOVA to evaluate the levels among the four time points. We also compared the SPP measurements stratified by comorbidities using the paired t-test and ANOVA.

To detect the predictors of foot ischemia recurrence, univariate predictors with p < 0.10 were included in a multivariate analysis using forced entry, and the results were presented as odds ratios (ORs) with 95% CIs. A multivariate model that included all significant variables and ORs was constructed, and the 95% CI was estimated. All statistical analyses were performed using JMP Version 14.0.0 software (SAS Institute Inc., Cary, NC, USA).

Results

Overall, 87 of the 183 screened patients met the eligibility criteria and were included in the study. The baseline characteristics of the study participants are summarized in Table 1, and the lesion and lower limb characteristics are summarized in Table 2. The prevalence of diabetes, hemodialysis, and ambulatory status in the study participants was 82.8%, 85.1%, and 77.0%, respectively (Table 1).

Table 1.

Patient characteristics.

Characteristic	n = 87
Age (years)	73.3 ± 12.1
Male, n (%)	57 (65.5)
Body mass index (kg/m²)	21.6 ± 4.0
Hypertension, n (%)	56 (64.4)
Diabetes mellitus, n (%)	72 (82.8)
Dyslipidemia, n (%)	18 (20.7)
Chronic kidney disease, n (%)	8 (9.2)
Hemodialysis, n (%)	74 (85.1)
Cerebrovascular disease, n (%)	16 (18.4)
Coronary artery disease, n (%)	50 (57.5)
Current smoker, n (%)	6 (6.9)
Ambulatory, n (%)	67 (77.0)
Cilostazol use, n (%)	17 (19.5)
DAPT use, n (%)	32 (36.8)
Statin use, n (%)	18 (20.7)

Continuous data are presented as the means ± standard deviation; categorical data are given as the counts (percentage).

DAPT: dual antiplatelet therapy.

Table 2.

Lesion and lower limb characteristics in the study participants.

Characteristic	n = 87
Target vessel, n (%)
Iliac + femoropopliteal + infrapopliteal artery	2 (2.3)
Femoropopliteal + infrapopliteal artery	46 (52.9)
Infrapopliteal artery	39 (44.8)
Multiple infrapopliteal artery	38 (43.7)
Lesion characteristics, n (%)
Iliac CTO	0 (0)
Femoropopliteal CTO	10 (11.5)
Femoropopliteal severe calcification	2 (2.3)
Infrapopliteal CTO	59 (67.8)
Infrapopliteal severe calcification	15 (17.2)
GLASS, n (%)
1	5 (5.7)
2	30 (34.5)
3	52 (59.8)
WIfI stage, n (%)
Stage 1	8 (9.2)
Stage 2	36 (41.4)
Stage 3	31 (35.6)
Stage 4	12 (13.8)

Data are presented as counts (percentage).

CTO: chronic total occlusion; GLASS: Global Limb Anatomic Staging System; WIfI: Wound, Ischemia, and foot Infection.

The prevalence of femoropopliteal and infrapopliteal lesions was the highest of all target lesions. Of all lesions, 38 lesions (43.7%) were performed for multiple infrapopliteal arteries. The frequencies of CTO and severe calcification in the infrapopliteal artery were 67.8% and 17.2%, respectively (Table 2).

The mean preprocedural dorsal and plantar SPP was 33.9 ± 14.7 and 33.4 ± 13.1 mmHg, respectively. The SPP significantly increased at 1 month but decreased during months 2 and 3 (mean dorsal SPP at 1, 2, and 3 months: 59.6 ± 20.3, 48.3 ± 20.9, and 39.7 ± 14.7 mmHg, respectively, p < 0.01; mean plantar SPP at 1, 2, and 3 months: 57.3 ± 18.2, 48.2 ± 15.6, and 40.5 ± 15.3 mmHg, respectively, p < 0.01) (Figure 2). As an overall trend, the same trends were observed when patients were stratified by their comorbidities. There were no significant differences in SPP before EVT and 1, 2, and 3 months after EVT when we divided them by sex, ambulatory status, prevalence of diabetes and dialysis, and GLASS classification (Figure 3).

Figure 2.

Overall skin perfusion pressure changes during follow-up.

Figure 3.

Comparison of skin perfusion pressure changes according to patient characteristics.

The prevalence of recurrent foot ischemia after EVT increased gradually and significantly (20.6%, 50.6%, and 70.1% at 1, 2, and 3 months, respectively, p < 0.01) (Figure 4).

Figure 4.

The prevalence of recurrent foot ischemia after endovascular treatment.

The recurrence of foot ischemia at 3 months was observed in 70 patients. The univariate analysis identified ambulatory status and severe infrapopliteal calcification as independent predictors, but the multivariate analysis identified severe infrapopliteal calcification as an independent predictor of recurrent foot ischemia 3 months after the procedure (OR, 3.8; 95% CI, 1.1–13.4; p = 0.04) (Table 3).

Table 3.

Multivariate analysis for the association between recurrence of foot ischemia at 3 months and clinical findings.

	Univariate			Multivariate
	OR	95% CI	p	OR	95% CI	p
Ambulatory	0.42	0.14–1.21	0.09	0.45	0.15–1.35	0.16
Diabetes	1.98	0.64–6.16	0.23
Hemodialysis	1.01	0.31–3.29	0.99
Statin use	0.51	0.17–1.52	0.23
DES use	0.36	0.09–1.44	0.15
Cilostazol use	0.42	0.76–7.53	0.12
DAPT use	0.75	0.31–1.80	0.52
GLASS 2 (vs 1)	1.15	0.17–7.89	0.89
GLASS 3 (vs 1)	1.39	0.21–9.01	0.73
WIfI 2 (vs 1)	0.89	0.19–4.14	0.89
WIfI 3 (vs 1)	1.38	0.29–6.58	0.68
WIfI 4 (vs 1)	2.01	0.32–12.5	0.46
Multiple infrapopliteal artery treatment	0.94	0.40–2.19	0.88
Infrapopliteal total occlusion	1.27	0.52–3.12	0.6
Infrapopliteal severe calcification	4.08	1.18–14.1	0.02	3.83	1.10–13.4	0.04
Wound healing	0.66	0.27–1.60	0.36

CI: confidence interval; DES: drug-eluting stent; DAPT: dual antiplatelet therapy; GLASS: Global Limb Anatomic Staging System; WIfI: Wound, Ischemia, and foot Infection; OR: odds ratio.

Discussion

In this study, we evaluated the longitudinal changes in the SPP after EVT and investigated the predictors of foot ischemia recurrence using prospective data from a single center.

Our study revealed three important findings. (1) The SPP after EVT in patients with CLTI significantly increased at 1 month, but decreased at months 2 and 3. Moreover, when stratifying the patients according to their comorbidities, the changes in the SPP after EVT did not differ. (2) The prevalence of recurrent foot ischemia at 1, 2, and 3 months after the procedure was approximately 20%, 50%, and 70%, respectively. (3) Infrapopliteal severe calcification was the sole predictor of foot ischemia recurrence 3 months after the procedure.

According to global vascular guidelines, arterial revascularization is the recommended firstline therapy to achieve wound healing or limb salvage in patients with CLTI.¹³ A Japanese multicenter study reported that infrapopliteal artery lesions accounted for more than 80% of lesions, including complex lesions of the femoropopliteal artery in patients with CLTI.⁸ A multicenter registry study by Iida et al. reported that the angiographic restenosis rate at 3 months after infrapopliteal angioplasty reached >70%.⁷ However, this study focused on angiographical data, and the percentage of patients who had foot ischemia recurrence based on the evaluation of hemodynamic measurements is unclear. Objective hemodynamic assessment of patients with CLTI is important for making decisions regarding revascularization and postprocedural evaluation. Although one study reported changes in the SPP up to 1 month after EVT, there are no reports on changes in the SPP thereafter. We demonstrated that the prevalence of recurrent foot ischemia evaluated by the SPP at 1, 2, and 3 months was approximately 20%, 50%, and 70%, respectively. Therefore, the concept of planned EVT might be plausible because more than half the patients with CLTI experience recurrent foot ischemia at 2 months after EVT.¹⁵ Furthermore, proper care of the wounds and meticulous follow-up after EVT appear to be of great importance for achieving wound healing.

We also analyzed the association between foot ischemia at 3 months and clinical findings. The results from our multivariate analysis show that severe infrapopliteal calcification is a predictor of recurrent foot ischemia after EVT in patients with CLTI. One explanation for this may be our inability to perform appropriate EVT for such a severely calcified lesion. To solve this problem, we recommend assessing the infrapopliteal vascular diameter using intravascular ultrasound (IVUS). Soga et al. reported that the use of IVUS made it possible to select the optimal balloon diameter, thereby obtaining a sufficient lumen gain.¹⁶ Moreover, an appropriate inflation technique is also important. A previous systematic review recommended slow inflation (1 atm every 5–10 s) and prolonged inflation time for at least 3 min for infrapopliteal angioplasty.¹⁷ In addition, a recent meta-analysis reviewed the usefulness of scoring balloons or atherectomy devices for vessel preparation which resulted in improved clinical outcomes.¹⁸ If applicable, stenting of the infrapopliteal artery could be a better option than plain balloon angioplasty in terms of a significant reduction in the time to reintervention for infrapopliteal lesions.¹⁹

Regarding the number of infrapopliteal artery treatments, a previous report demonstrated that the most amenable artery should be treated rather than the number of treated vessels.²⁰

Our study is the first to demonstrate longitudinal changes in the SPP after EVT and investigate the predictors of recurrent foot ischemia as assessed by the SPP. One month after EVT, foot ischemia progresses gradually every month, regardless of the underlying patient characteristics. Objective foot ischemia evaluation should be performed regularly during meticulous follow-up and revascularization, as appropriate.

However, our findings should be comprehensively and systematically evaluated, using prospective and large-volume databases.

Study limitations

This study has some limitations. First, this was an observational study, which might have introduced traditional biases, such as selection bias. Second, the follow-up period was only 3 months, and a relatively small number of patients was evaluated in this study although the number of cases exceeded the calculated sample size. Further, a longer follow-up and a larger number of studies are required to evaluate longitudinal changes after EVT in patients with CLTI. Third, the differences in the aggressiveness of revascularization may have affected our results. It is possible that some operators tried to completely revascularize the dorsalis pedis or plantar artery, while others might have simply treated the stenosis or short-segment occlusion. Fourth, we could not use DCBs, DESs, or atherectomy devices to treat infrapopliteal lesions in Japan; thus, there might have been differences in patency rates. Finally, we did not include patients who underwent endovascular procedures performed by interventional radiologists.

Conclusion

The SPP after EVT in patients with CLTI significantly increased at 1 month and decreased at months 2 and 3, regardless of patient comorbidities. The prevalence of recurrent foot ischemia detected by the SPP at 1, 2, and 3 months was approximately 20%, 50%, and 70%, respectively. Severe infrapopliteal calcification is the sole predictor of foot ischemia recurrence. Meticulous follow-up after EVT and regular hemodynamic examinations are important.

Footnotes

Acknowledgments

The author(s) thank the staff of the catheterization laboratories of each hospital for their assistance with this study.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

This study was approved by the Medical Ethics Committee of Nagoya Heart Center and was conducted in accordance with the latest version of the Declaration of Helsinki. Written informed consent was obtained from each patient or their relative before EVT.

ORCID iD

Takahiro Tokuda

Author biographies

Takahiro Tokuda is a medical doctor at Nagoya Heart Center. He is an interventional cardiologist and focuses specially on peripheral artery disease and its intervention field.

Yasuhiro Oba is a medical doctor at Nagoya Heart Center. He is an vascular surgeon and focuses specially on peripheral artery disease and its intervention field.

Ai Kagase is a medical doctor at Nagoya Heart Center. She is an interventional cardiologist and focuses specially on structural heart artery disease and its intervention field.

Hiroaki Matsuda is a medical doctor at Nagoya Heart Center. He is an interventional cardiologist and focuses specially on coronary intervention.

Yoriyasu Suzuki is a medical doctor at Nagoya Heart Center. He is an interventional cardiologist and focuses specially on coronary intervention.

Akira Murata is a medical doctor at Nagoya Heart Center. He is an interventional cardiologist and focuses specially on coronary intervention.

Tatsuya Ito is a medical doctor at Nagoya Heart Center. He is an interventional cardiologist and focuses specially on coronary intervention.

Keisuke Hirano is a medical doctor at Toyohashi Heart Center. He is an interventional cardiologist and focuses specially on peripheral artery disease and its intervention field.

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