Efficacy of Rheocarna^®, a Novel Apheresis Device, in Patients With No- or Poor-Option Chronic Limb-Threatening Ischemia

Abstract

Background: Although revascularization is first-line therapy for chronic limb-threatening ischemia (CLTI), there are no established treatments for patients in whom revascularization is not (or is a poor) option, including CLTI that has responded poorly to revascularization. This study verified the efficacy of the Rheocarna^®, a novel apheresis device, for no-option CLTI or poor-response CLTI after revascularization.

Methods and Results: This multicenter retrospective observational study analyzed 221 patients (221 limbs) with no- or poor-option CLTI (mean [±SD] age 71±10 years; males, 70.1%; diabetes, 76.5%; dialysis, 87.8%; Rutherford category 6, 26.4%) undergoing apheresis with the Rheocarna between March 2021 and March 2022. The primary endpoint was the 1-year wound-healing rate. After apheresis with the Rheocarna, C-reactive protein, fibrinogen, and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly, and the ankle-brachial index (ABI) and skin perfusion pressure (SPP) increased significantly (all P<0.05). At 1 year, the wound-healing rate was 60.7%, and rates of limb salvage, freedom from reintervention, overall survival, and amputation-free survival were 83.4%, 69.2%, 70.2% and 61.3%, respectively. At baseline, non-ambulatory status, lower ejection fraction, and lower blood albumin levels were independently associated with a lower wound-healing rate.

Conclusions: Apheresis with the Rheocarna in patients with no- or poor-option CLTI reduced LDL-C and fibrinogen levels and improved ABI and SPP, achieving a 1-year wound healing rate of 60.7%. This novel approach could provide additional treatment options for conventional CLTI.

The primary goal of treatment of chronic limb-threatening ischemia (CLTI) complicated by ischemic unhealed ulcer and/or gangrene is wound healing, and the first-line treatment is surgical or endovascular revascularization. Sufficient blood flow to the wound through successful revascularization can contribute to complete wound healing.^1–4 However, revascularization is not successful in all CLTI patients. CLTI patients who do not have the option of revascularization, including those who responded poorly to revascularization, have a higher rate of major amputation, and there is a marked risk of major amputation particularly in patients dependent on dialysis.^5,6 Apheresis is one of the potential treatment options for these patients. Apheresis selectively removes lipoproteins, such as low-density lipoprotein cholesterol (LDL-C), thereby reducing plasma viscosity and improving hemorheology.⁷ It was also reported that apheresis reduced the risk of reintervention and major amputation in CLTI patients undergoing endovascular therapy (EVT), because it improves the inflammatory state.⁸ However, conventional LDL-C apheresis, using an adsorption-based technique, has not been widely used because of the size of the system required to separate plasma from blood and the large extracorporeal circulation volume, in addition to it being to complicated operate. The Rheocarna^® (Kaneka Medix, Osaka, Japan), a novel apheresis device, does not require plasma separation, which significantly reduces the extracorporeal circulation volume, allowing the use of a regular blood circulation system, and simplifies the operation. The Rheocarna can remove both fibrinogen and LDL-C. Fibrinogen is the molecule that has the greatest impact on plasma viscosity,⁹ and decreasing circulating fibrinogen levels can reduce blood viscosity. However, there are few reports of this new apheresis treatment in CLTI patients.

The aim of this study was to determine whether the novel Rheocarna apheresis device improved CLTI outcomes in patients with no or poor options for revascularization.

Methods

This study analyzed data from the mulTicenter retrospective stUdy of RheocarNa In Patients with chronic limb threatening ischemia (TURNIP). TURNIP was a multicenter retrospective observational study that included adult patients (age ≥20 years) who underwent apheresis with the Rheocarna for CLTI with ischemic unhealed ulcers or gangrene (Rutherford category 5–6), including CLTI that responded poorly to revascularization, between March 2021 and March 2022 at 24 cardiovascular centers across Japan. Patients with acute limb ischemia, obvious thrombotic occlusion, anastomosis stenosis after bypass surgery, planned major amputation, a history of plasma exchange therapy, serious cardiac disease, severe liver disorders, extreme anemia, malignant tumors, and hemorrhagic disease were excluded from the registry. In addition, patients who could not discontinue angiotensin-converting enzyme inhibitors (ACEi) were not included in the registry (because the bradykinin produced is not eliminated properly and causes severe hypotension, and the use of ACEi is listed as a contraindication for apheresis). Wound management and other adjuvant therapies were performed at the discretion of each facility.

In all, 221 limbs in 221 patients with no-option CLTI were treated with the Rheocarna during the study period, and included in the present study. The decision to use the Rheocarna was left to the discretion of the attending vascular specialists.

Hemodynamic status was assessed with the ankle-brachial index (ABI) and skin perfusion pressure (SPP).¹⁰ The severity of arterial lesions was assessed using the Global Limb Anatomic Staging System (GLASS) for infrainguinal lesions.¹ Wound severity was assessed using both the Rutherford classification and the Wound, Ischemia and foot Infection (WIfI) classification.^1,11 All CLTI patients were treated with antibiotics for as long as necessary because of potential infection.

This study was conducted in accordance with the Declaration of Helsinki, and was approved by the Institutional Review Board of Kokura Memorial Hospital (Reference no. 22012701). The requirement for informed consent was waived because of the retrospective nature of the study; instead, relevant information regarding the study was publicly available, with opportunities for patients to opt out as per domestic ethical guidelines.

Apheresis With the Rheocarna

Figure 1 shows an overview of treatment with the Rheocarna. The Rheocarna consists of a polypropylene column packed with cellulose beads (mean particle size 450 μm). Negatively charged dextran sulfate and hydrophobic L-tryptophan are chemically fixed to the surface of the cellulose beads. When blood passes through the column, LDL-C with positively charged apolipoprotein B is adsorbed; fibrinogen is also adsorbed by hydrophobic interaction with tryptophan. Apheresis was performed up to 2 h per session, twice a week, for a period of 3 months (maximum 24 treatments), followed by 12 months of observation. The quantity of blood flow (QB) was started at 30–50 mL/min, and if blood pressure did not fall, QB was increased to 50–100 mL/min (maximum 200 mL/min). Heparin was administered continuously at 500–1,500 units/h after an initial bolus dose of 2,000–3,000 units; patients in whom heparin could not be used were treated with nafamostat. An arterio-venous shunt was used as an access site in dialysis patients. In non-dialysis patients, a double-lumen catheter was implanted and used as the access site.

Figure 1.

Product overview. apo-B, apolipoprotein B; LDL-C, low-density lipoprotein cholesterol.

Outcome Measures

The primary outcome measure was the wound-healing rate at 1 year. Major amputation was treated as a permanent failure of wound healing. Secondary outcome measures included 1-year rates of limb salvage (freedom from major amputation), freedom from major adverse limb events (MALE), freedom from reintervention, amputation-free survival, and overall survival. Surrogate endpoints were changes in ABI, SPP, fibrinogen, and LDL before and after Rheocarna. Angiographic assessments were performed by an independent physician who was not involved in the study, and patients were divided into 3 groups: improvement, no change, or worsening. “Improvement” was further divided into 4 categories: improved blood flow velocity; extended contrast area; wound blush; and venous return (which was defined as injected contrast returning via a vein through the wound).

Definitions

CLTI was diagnosed by vascular specialist when patients had ischemic foot ulcer/gangrene with an ABI <0.9 and SPP <40 mmHg or when patients had ischemic ulcer/gangrene with critical ischemia indicated by other modalities. A decrease in blood pressure was defined as a decrease in systolic blood pressure of ≥30 mmHg from the level before starting Rheocarna treatment. Non-ambulatory patients were defined as those who could barely walk on their own, including those in wheelchairs and those who were bedridden. Major amputation was defined as surgical excision of the limb above the ankle. Minor amputation was defined as below-ankle amputation of the index limb. Wound healing was defined as the complete epithelialization of the reference wound. MALE was defined as a composite of major amputation or any reintervention during the study period.

Statistical Analyses

Unless indicated otherwise, continuous variables are presented as the mean±SD or the median with interquartile range (IQR), whereas categorical variables are presented as percentages. Two-tailed P<0.05 was considered statistically significant, and 95% confidence intervals (CIs) are reported where appropriate. Variables before and after Rheocarna treatment were compared using paired t-tests. Time-to-events was estimated using the Kaplan-Meier method. Associations of baseline characteristics with wound healing were investigated using Cox proportional hazards regression models. Variables that were statistically significant in the univariable model were subsequently entered into the multivariable model. Missing data were addressed by listwise deletion. All statistical analyses were performed with R version 4.1.1 (R Development Core Team, Vienna, Austria).

Results

The baseline characteristics of the study population are summarized in Table 1. The mean patient age was 71±10 years, and 70.1% of the study participants were male. The prevalence of diabetes and dialysis was 76.5% and 87.8%, respectively. Rutherford category 6 accounted for 26.4% of cases. Revascularization was attempted in 178 (80.5%) patients (endovascular, n=176; surgical, n=1; hybrid, n=1). Details of Rheocarna treatment and adjunct therapy are presented in Table 2. In patients who underwent revascularization, the Rheocarna was started a median of 10 days (IQR 4–29 days) after revascularization. The median number of Rheocarna treatments was 8 (IQR 5–19), and the median duration was 1.1 months (IQR 0.5–2.2 months). The major indication for Rheocarna treatment was clinical failure after revascularization (60.2%). As indicated in Table 3, ABI and SPP increased significantly after Rheocarna treatment, whereas C-reactive protein, fibrinogen, and LDL-C levels decreased significantly (all P<0.05).

Table 1.

Baseline Characteristics (n=221 Patients, 221 Limbs)

Characteristic	Value	Missing data (n)
Age (years)	71±10
Male sex	155 (70.1)
BMI (kg/m2)	21.9±3.9
Non-ambulatory	85 (38.5)
Smoking history	126 (57.0)
Receiving welfare	23 (10.4)
Hypertension	167 (75.6)
Dyslipidemia	128 (57.9)
Diabetes	169 (76.5)
Renal failure and on dialysis	194 (87.8)
Cerebrovascular disease	63 (28.5)
Coronary artery disease	131 (59.3)
Chronic heart failure	85 (38.5)
Ejection fraction (%)	54±13	5
Hemoglobin (g/dL)	10.5±1.7	3
Albumin (g/dL)	3.1±0.6	3
Medication
Aspirin	139 (62.9)
P2Y12 inhibitor	141 (63.8)
Cilostazol	22 (10.0)
Warfarin	53 (24.0)
DOAC	4 (1.8)
Statin	99 (44.8)
ACEi	7 (3.2)
ARB	55 (24.9)
Revascularization
Endovascular	176 (79.6)
Aortoiliac	12 (5.4)
Femoropopliteal	69 (31.2)
Infrapopliteal (tibial)	144 (65.2)
Inframalleolar (pedal)	58 (26.2)
Surgical	1 (0.5)
Hybrid	1 (0.5)
Impossible	43 (19.5)
History of minor amputation	53 (24.2)	2
Rutherford category
5	163 (73.8)
6	58 (26.2)
WIfI classification, W grade		2
W-1	87 (39.7)
W-2	90 (41.1)
W-3	42 (19.2)
WIfI classification, I grade		12
I-1	86 (41.1)
I-2	42 (20.1)
I-3	81 (38.8)
WIfI classification, fI grade		3
fI-0	65 (29.8)
fI-1	80 (36.7)
fI-2	60 (27.5)
fI-3	13 (6.0)
WIfI classification, clinical stage		12
Stage I	19 (9.1)
Stage II	25 (12.0)
Stage III	43 (20.6)
Stage IV	122 (58.4)
GLASS classification, FP		3
Grade 0	158 (72.5)
Grade 1	42 (19.3)
Grade 2	8 (3.7)
Grade 3	6 (2.8)
Grade 4	4 (1.8)
GLASS classification, IP		3
Grade 0	58 (26.6)
Grade 1	29 (13.3)
Grade 2	26 (11.9)
Grade 3	26 (11.9)
Grade 4	79 (36.2)
GLASS classification		5
Stage 0	55 (25.5)
Stage 1	46 (21.3)
Stage 2	35 (16.2)
Stage 3	80 (37.0)
GLASS classification, IM		5
P0	38 (17.6)
P1	99 (45.8)
P2	79 (36.6)

Unless indicated otherwise, data are given as n (%), mean±SD. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BMI, body mass index; DOAC, direct oral anticoagulants; FP, femoropopliteal; GLASS, Global Limb Anatomic Staging System; IM, inframalleolar; IP, infrapopliteal; WIfI, Wound, Ischemia and foot Infection.

Table 2.

Rheocarna Treatment and Adjunct Therapy (n=221)

Rheocarna treatment
No. sessions	8 [5–19]
Period of treatment (months)	1.1 [0.5–2.2]
Anticoagulation
Heparin	191 (86.4)
Nafamostat	38 (17.2)
Indications
Clinical failure after revascularization	133 (60.2)
Procedure failure	18 (8.1)
No indication for revascularization due to poor patient condition	5 (2.3)
No indication for revascularization due to poor vascular condition	52 (23.5)
Any ≥2 of the above indications	13 (5.9)
Adjuvant therapy
Negative pressure wound therapy	59 (26.8)
Hyperbaric oxygen therapy	60 (27.4)
Lumbar sympathetic ganglion block	1 (0.5)
Spinal cord stimulation	4 (1.8)
Off-loading	143 (65.3)
Carbonated spring bath	5 (2.3)
Rehabilitation	185 (84.5)

Values are presented as n (%) or the median (interquartile range).

Table 3.

Parameters Before and After Rheocarna Treatment

	Before Rheocarna	After Rheocarna	P value
Ankle-brachial index	0.90±0.27	0.95±0.23	0.020
<0.40	3 (2.1)	1 (0.7)	0.017
0.40–0.59	9 (6.2)	5 (3.4)
0.60–0.79	42 (29.0)	28 (19.3)
≥0.80	91 (62.8)	111 (76.6)
SPP (mmHg)
Dorsal	43±19	52±24	0.001
Plantar	45±19	50±19	0.011
C-reactive protein (mg/dL)	3.65±4.33	1.80±2.75	<0.001
Fibrinogen (mg/dL)	420±129	300±97	<0.001
LDL-C (mg/dL)	73±34	51±23	<0.001

Unless indicated otherwise, values are presented as n (%) or the mean±SD. LDL-C, low-density lipoprotein cholesterol; SPP, skin perfusion pressure.

During Rheocarna treatment, 73 (33.0%) patients exhibited a decrease in blood pressure (>30 mmHg). All decreases in blood pressure occurred within 1 h of starting Rheocarna treatment. Of the 73 patients who experienced a decrease in blood pressure, 15 (20.5%; 6.8% of the entire study cohort) discontinued Rheocarna treatment due to difficulty continuing with the treatment. In the case of the remaining patients who experienced a decrease in blood pressure, Rheocarna treatment could be continued by decreasing the QB. Within 3 months, 33 (14.9%) patients completed all 24 sessions of Rheocarna treatment, whereas the remaining 188 patients discontinued Rheocarna treatment. The reasons for discontinuation were wound healing (21.3%; 40/188), decreased blood pressure (8.0%; 15/188), patient refusal (7.4%; 14/188), others (e.g., difficulty in continuing after discharge; 54.8%; 103/188), and unknown (8.5%; 16/188).

Efficacy

During a median follow-up of 14.3 months (IQR 4.9–19.8 months), 117 patients experienced wound healing, 32 underwent major amputation, and 83 died. The leading cause of death was infection (n=32; 38.6%), following cardiovascular disease (n=26; 31.3%), others (n=13; 15.7%), and unknown causes (n=12; 14.5%). Figure 2 illustrates the Kaplan-Meier estimates of time-to-events. At 1 year, cumulative rates were was 60.7% (95% CI 52.5–67.5%) for wound healing (Figure 2A), 83.4% (95% CI 78.0–89.1%) for limb salvage (Figure 2B), 69.2% (95% CI 61.7–77.7%) for freedom from reintervention (Figure 2C), 54.6% (95% CI 46.6–63.9%) for freedom from MALE (Figure 2D), 70.2% (95% CI 64.2–76.8%) for overall survival (Figure 2E), and 61.3% (95% CI 54.9–68.4%) for amputation-free survival (Figure 2F). As indicated in Table 4, non-ambulatory status at baseline was inversely associated with wound healing, whereas baseline ejection fraction and serum albumin levels were positively associated with wound healing. The adjusted hazard ratios (HRs) were 0.55 (95% CI 0.37–0.84; P=0.005) for non-ambulatory status, 1.28 (95% CI 1.10–1.49; P=0.001) per 10% increase in ejection fraction, and 1.42 (95% CI 1.01–1.99; P=0.043) per 1-g/dL increase in serum albumin level.

Figure 2.

Kaplan-Meier estimates of cumulative incidence of (A) wound healing, (B) limb salvage, (C) freedom from major adverse limb events (MALE), (D) freedom from reintervention, (E) amputation-free survival, and (F) overall survival. Dashed lines represent 95% confidence intervals.

Table 4.

Associations Between Baseline Characteristics and Wound Healing

	Unadjusted		Adjusted
	HR (95% CI)	P value	HR (95% CI)	P value
Age (per 10-year increase)	1.05 (0.88–1.26)	0.59	N/I
Male sex	0.88 (0.58–1.32)	0.53	N/I
BMI (per 5-kg/m2 increase)	0.99 (0.78–1.24)	0.91	N/I
Non-ambulatory	0.59 (0.39–0.88)	0.010	0.55 (0.37–0.84)	0.005
Smoking history	1.19 (0.82–1.72)	0.37	N/I
Receiving welfare	1.35 (0.76–2.40)	0.31	N/I
Hypertension	0.91 (0.60–1.37)	0.64	N/I
Dyslipidemia	0.75 (0.52–1.08)	0.13	N/I
Diabetes	0.98 (0.63–1.53)	0.94	N/I
Renal failure and on dialysis	0.93 (0.54–1.60)	0.80	N/I
Cerebrovascular disease	0.74 (0.48–1.12)	0.15	N/I
Coronary artery disease	0.70 (0.48–1.01)	0.054	N/I
Chronic heart failure	0.70 (0.47–1.03)	0.067	N/I
Ejection fraction (per 10% increase)	1.23 (1.07–1.42)	0.004	1.28 (1.10–1.49)	0.001
Hemoglobin (per 1-g/dL increase)	1.02 (0.92–1.13)	0.70	N/I
Albumin (per 1-g/dL increase)	1.45 (1.03–2.03)	0.034	1.42 (1.01–1.99)	0.043
Aspirin use	1.02 (0.70–1.49)	0.91	N/I
P2Y12 inhibitor use	1.20 (0.82–1.76)	0.35	N/I
Cilostazol use	1.73 (0.99–3.03)	0.055	N/I
Warfarin use	0.75 (0.48–1.19)	0.23	N/I
DOAC use	0.34 (0.05–2.41)	0.28	N/I
Preceding revascularization	0.78 (0.49–1.25)	0.30	N/I
History of minor amputation	0.90 (0.59–1.39)	0.64	N/I
Rutherford category 6	0.86 (0.57–1.29)	0.46	N/I
WIfI classification
W grade	0.80 (0.63–1.02)	0.077	N/I
I grade	1.13 (0.92–1.39)	0.24	N/I
fI grade	0.87 (0.71–1.07)	0.18	N/I
WIfI clinical stage	0.94 (0.78–1.13)	0.50	N/I
GLASS classification	0.91 (0.79–1.06)	0.25	N/I
FP	0.94 (0.73–1.22)	0.65	N/I
IP	0.94 (0.84–1.05)	0.29	N/I
IM	0.81 (0.64–1.03)	0.089	N/I
Duration of Rheocarna treatment (per 1 month)	1.02 (0.86–1.21)	0.79	N/I

CI, confidence interval; HR, hazard ratio; N/I, not included. Other abbreviations as in Table 1.

Angiographic Assessment

In 36 of 221 (16.3%) patients, below-the-ankle angiography was performed before and after Rheocarna treatment. Of these 36 patients, 31 (88%) were classified as exhibiting “improvement” and 5 (13.9%) as exhibiting “no change.” None of the patients exhibited “worsening” (Figure 3A). In the improved group, an improvement in blood flow velocity was observed in all cases. This included improved blood flow velocity (n=31), extended contrast area (n=22), wound blush (n=13), and venous return (injected contrast returning as a vein through the wound; n=5). Representative images before and after Rheocarna treatment are shown in Figure 3B–D: wound blush and venous return after Rheocarna treatment in a 70-year-old woman (Figure 3B); extended contrast area and accumulation of contrast around the wound after Rheocarna treatment in an 80-year-old woman (Figure 3C); and extended contrast area after Rheocarna in an 80-year-old man (Figure 3D).

Figure 3.

Below-the-ankle angiographic assessment after Rheocarna treatment and representative cases. (A) Angiographic improvement after Rheocarna. (B) 70-yearsmale; After the procedure before Rheocarna, there is no wound blush. And after Rheocarna, wound blush was angiographically observed (arrow). (C) 80-year male; Below-the-ankle arteries were difficult to identify from final angiography after the procedure before Rheocarna. However, the accumulation of contrast media around the wound was obviouly found after the Rheocarna treatment (dotted circle). (D) 80-year male; No digital artery was identified from final angiography after the procedure before Rheocarna. However, after the Rheocarna treatment,all digital arteries was clearly observed (dotted circle). DM, diabetes mellitus; HD, hemodialysis; yrs, years.

Discussion

This study examined 12-month outcomes and associated factors in patients with no-option CLTI receiving Rheocarna treatment in a real-world setting. A notable feature of this study was the inclusion of a large number of patients with renal failure who were on dialysis. Patients with renal failure and on dialysis are often complicated by diabetes and dyslipidemia, leading to vascular endothelial dysfunction and atherosclerosis. In addition, the inflammatory state caused by uremia induced by renal failure, the endothelial dysfunction modified by insulin resistance and platelet aggregation, and vessel calcification strongly accelerate the progression to CLTI.^12,13 Furthermore, infrapopliteal lesions in these patients are often complex and difficult to treat due to heavy calcification and longer occlusion involving inframalleolar arterial disease. Even when revascularization is successful, the restenosis rate is extremely high^14,15 and wound healing is significantly delayed compared with patients who are not on dialysis.^5,6 Historically, it has been estimated the 1-year rates are 13.8% for limb salvage, 30% for major amputation, and 50% for mortality in patients with no-option CLTI.¹⁶ Our study demonstrated a 1-year limb salvage rate of 83.4% and overall survival of 70.2%. Assuming a similar patient population, the outcomes for patients in our study were better than the historical findings. Similarly, a recent report of the use of the Rheocarna in dialysis patients also revealed a better ulcer healing rate (45.9%) than historical data, without safety concerns.¹⁷ These findings are in agreement with our own findings of the safety and effectiveness of Rheocarna.

In the present study, multivariable analysis showed that the predictors of wound healing at baseline were non-ambulatory status, low ejection fraction, and low serum albumin. None of the other baseline variables, such as Rutherford category, WIfI classification, or GLASS classification, were significant predictors of wound healing, suggesting that the effectiveness of apheresis with the Rheocarna was not strongly influenced by lesion background or wound severity. These results suggest that non-ambulatory patients and patients with uncontrolled heart failure and/or malnutrition have lower wound healing rates and are unlikely to benefit from adjunctive therapy. This novel apheresis device could be a good option for patients with no-option CLTI, including CLTI that has responded poorly to revascularization. We mean that in terms of wound healing, there is no significant difference between GLASS and WIfI. This finding suggests that wound healing may have improved in severe cases (as much as in mild or moderate cases), even though it is generally believed that the severity of the wound affects wound healing. Because the present study was conducted on a small number of patients, further investigations are needed to increase the number of cases.

Mechanism

The novel apheresis device used in this study improves blood viscosity primarily by lowering LDL-C and fibrinogen. In addition, it reduces inflammatory cytokines that often appear after revascularization¹⁹ and improves the microcirculation by reducing local inflammation in the wound.²⁰ Fibrinogen-induced hemorheological disturbances have been major problems in the microcirculation (e.g., arterioles and capillaries).²¹ This novel apheresis treatment is expected to work well in the microcirculation.

In the present study, the use of a novel apheresis device not only decreased LDL-C and fibrinogen levels but also decreased levels of C-reactive protein, a marker of inflammation, resulting in a significant increase in ABI and SPP. The proportion of patients exhibiting improvements in these parameters, and the degree of improvement, are similar to those reported in a recent study.²²

Our findings suggest that the improvement in blood viscosity in the microcirculation increased blood flow to the wound tissue, which improved the inflammatory state and contributed to accelerated healing. However, a single or a few sessions of apheresis are not sufficient. It is important to continuously perform apheresis, because repeated sessions gradually improve the microcirculation and promote wound healing. Angiographic improvement in blood flow has also been reported with continuous apheresis.²³

Clinical Implications

The strength of Rheocarna treatment is its improvement of the microcirculation. This is likely to be beneficial not only for patients with CLTI without the option of revascularization, but also for patients with CLTI undergoing revascularization for larger vessels. Patients with CLTI often have an impaired microcirculation, together with diseased larger vessels. Revascularization can only treat larger vessels. A dual approach to the microcirculation (angiographically invisible vessels) and angiographic inflow (visible vessels), using the add-on of Rheocarna treatment to revascularization, would be useful for CLTI that has responded poorly to revascularization. The main target vessels of apheresis (arterioles or the microcirculation) and revascularization (the infrapopliteal or inframalleolar artery) are different, and therefore synergistic effects are expected when apheresis is used in combination with revascularization.

Recently, there have been reports of the effectiveness of drug-eluting stents in reducing restenosis in infrapopliteal lesions.²⁴ Although only balloon angioplasty was used in present study, combination therapy of reducing restenosis of infrapopliteal lesions by drug-eluting stents and improving the microcirculation by apheresis is expected to have an additive effect on wound healing. Further investigations are needed to verify the efficacy of these approaches. Deep venous arterialization (DVA) is also attracting clinical attention.²⁵ Although no patients were treated with DVA in the present study, an improvement in microcirculation may support the efficacy of DVA and should be considered in future studies.

Study Limitations

This study has several limitations. First, this study was a retrospective observational study. There could be bias in patient selection and potential outcomes. Further large-scale prospective randomized trials should produce more reliable results. Second, a multidisciplinary approach was taken at all centers in consultation with vascular specialists regarding revascularization methods, procedure endpoints, and wound management, but the decisions about treatment strategy were made by each center. Therefore, the strategies for CLTI may not be the same. In some cases, adjuvant therapies (e.g., hyperbaric oxygen therapy, spinal cord stimulation, lumbar sympathetic ganglion block) were given concurrently. In addition, the indications for revascularization and wound management were determined by the foot care team at each institution. Because this study was conducted primarily by cardiologists, the results may have been affected by differences in the timing of repeat revascularization by vascular surgeons or plastic surgeons, decisions regarding wound management (e.g., debridement or minor amputation), and the introduction of Rheocarna, which were not standardized in this study. Future studies need to take these factors into consideration. In the present study, no combination of adjuvant therapies was assessed, and future studies are needed into the type and combination of adjuvant therapies. Finally, although atherosclerotic CLTIs were the main focus of this study, it has been reported that non-atherosclerotic CLTIs have a poor outcome.^26,27 Future studies are needed to determine whether apheresis with the Rheocarna has similar effects in non-atherosclerotic CLTI and acute limb ischemia.

Conclusions

This study has demonstrated the efficacy of the Rheocarna, a novel apheresis device, in patients with no-option CLTI, including CLTI that responded poorly to revascularization. This new apheresis device reduced LDL-C and fibrinogen levels and improved ABI and SPP, achieving a 1-year wound healing rate of 60.7%. This new approach to the microcirculation could provide future options for conventional CLTI treatment.

Sources of Funding

This study did not receive any specific funding.

Disclosures

Y.S., O.I., D.K., and M.F. have received honoraria from Kaneka Medics. The other authors have no conflicts of interest to report.

IRB Information

This study was approved by the Institutional Review Board of Kokura Memorial Hospital (Reference no. 22012701).

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