Interventional procedure overview of percutaneous deep venous arterialisation for chronic limb-threatening ischaemia
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Evidence summary
Population and studies description
This interventional procedure overview is based on 108 patients with CLTI who had the procedure and were reported in 6 studies including 1 feasibility study, 1 pilot study, and 4 case series. The flow chart of the literature selection process for this rapid review of the literature is shown in figure 1. The key evidence is presented in table 2 and table 3, and another 15 relevant studies are listed in table 5.
Studies were carried out in US, Japan, Singapore, and European countries (France, German, Italy and Netherlands). Of the 6 studies included in the main evidence, 2 studies were retrospective in nature. The recruitment period ranged from 2013 to 2020. Each study included a small sample size, ranging from 5 to 32 patients. Of the 108 patients, 69 patients were male and 39 patients were female. Their age ranged from mean 58 to 82 years in 5 studies and had a median age of 85 years in 1 study (Kum 2017). The longest follow up was median 34 months (Schmidt 2020), followed by median 20 months (Kum 2017). In other studies follow up was limited to about 12 months.
All patients had CLTI with no other options for arterial revascularisation techniques (so called 'no-option CLTI') because of the absence of a viable distal target vessel, viable conduit, or other comorbidities. Most studies included patients with Rutherford category 5 or 6 CLTI, and 1 study selected patients with Rutherford category 4 to 6 CLTI, with Rutherford category 4 in 1 patient (Del Giudice 2018). Notable comorbidities were, but not limited to, diabetes, hypertension and renal insufficiency. Table 2 presents study details.
Study no. | First author, date country | Patients (male: female) | Age, (years) | Study design | Inclusion criteria | Intervention | Follow up |
|---|---|---|---|---|---|---|---|
1 | Clair (2021) US (7 centres) | n=32 (32 limbs) 21:11 | Mean 71 | Single-arm, feasibility study (PROMISE I; NCT03124875) | Adult patients with no-option CLTI (beyond medical management) | PDVA using the LimFlow system | 12 months |
2 | Schmidt (2020) Netherlands, Germany, France and Singapore (4 centres) | n=32 (32 limbs) 20:12 | Mean 67 | Case series (retrospective; ALPS) | Rutherford category 5 or 6 CLTI, no angiographically evident distal target artery for endovascular therapy or a distal bypass, and at least 1 patent tibial artery in the proximal segment. | PDVA using the LimFlow system | Median 34 months (range 16 to 63) |
3 | Nakama (2022) Japan (multiple centres) | n=18 (18 limbs) 14:4 | Mean 75.5 | Case series (retrospective; DEPARTURE Japan) | Patients with CLTI who underwent PDVA during the study period and with tissue loss (Rutherford 5 or 6). | 12 months | |
4 | Cangiano (2021) Italy (single centre) | n=14 8:6 | Mean 82 | Case series | Patients with CLTI (Rutherford category 5 or 6; TASC II C-D infrapopliteal disease) who were at risk of major amputation without revascularisation; the presence of a patent posterior tibial artery vessel proximally as an inflow vessel for AVF; at least 1 prior endovascular or surgical failed attempt for revascularisation due to lesion recoil despite optimal balloon angioplasty and/or absence of a reasonable target foot vessel for bypass or angioplasty. | PDVA using Pioneer Plus for AVF creation | Mean 12 months |
5 | Del Giudice (2018) 2 European centres | n=5 4:1 | Mean 58 | Case series | CTLI Rutherford 4 to 6; severe disease associated to lack of vessel outflow; no-options patients; proximal patency of at least 1 BTK vessel | PDVA using the LimFlow system | Mean 10 months (range 1 to 21) |
6 | Kum (2017) Singapore (single centre) | n=7 2:5 | Median 85 | Open-label, single-arm pilot study | Adult patients aged 21 to 100 years with CLTI (Rutherford category 5 or 6) who were at risk of major amputation without revascularisation, had at least 1 patent tibial vessel as an inflow vessel for PDVA, and had no conventional endovascular or surgical options for revascularisation due to lesion recoil despite optimal balloon angioplasty and/or absence of a reasonable target foot vessel for bypass or angioplasty. | PDVA using the LimFlow system or ordinary devices | Median 20 months (IQR 6 to 32) |
Efficacy outcomes | Safety outcomes | |
|---|---|---|
Technical success: 97% (31/32) Technical failure: 4% (1/32) related to an inability to achieve venous access beyond the ankle Procedural success: 75% (24/32) AFS rate:
WIfI scoring:
Core lab-adjudicated wound healing status of 'fully healed' or 'healing':
Minor amputations: n=19 in 15 patients
Reintervention (plain balloon angioplasty, drug-coated balloons, drug-eluting stents, cutting balloon, or atherectomy) rate: 52% (16/31) with 88% (14/16) of the maintenance reinterventions occurring within the first 3 months. Most reinterventions (n=12; 75%) involved the arterial inflow tract proximal to the stented LimFlow circuit, and no in-stent stenoses were determined to have been the cause of reintervention. | ||
Schmidt (2020) | Technical success: 97% (31/32) Technical failure: 3% (1/32) because the target vein did not respond to aggressive balloon dilation, which precluded stent-graft implantation. This patient was excluded from further analysis. AFS estimates:
Survival estimates:
Limb salvage estimates:
All major amputations were done within 9 months of the procedure. Complete wound healing: Among the 21 patients who remained alive without amputation, the majority (18, 85.7%) had completely healed wounds at 12 months. TcPO2: Mean number of TcPO2 measurements per patients: 10.9
This became statistically significantly higher after 45 days (increase of 22.1 mmHg, p=0.027) and remained statistically significantly higher during follow up (increase of 41.7 mm Hg, p<0.001) compared with baseline. DVA circuit occlusion: n=21 with a median of 2.6 months to occlusion Reintervention:
| Non-fatal myocardial infarction within 30 days: n=2 Death: n=7 due to progression of foot sepsis (n=1), a perforated diverticulum of the bowel despite laparotomy (n=1), myocardial infarction (n=2), pneumonia (n=2), and exacerbation of COPD (n=1) Adverse events:
|
Nakama (2022) | Technical success: 88.9% (16/18) Reason for procedural failure: valvulotomy failure (5.6%; n=1) and AVF creation failure (5.6%; n=1) 30-day major amputation rate: 22.2% (n=4) Causes: uncontrollable ischaemia, 16.7% (n=3); uncontrollable infection, 5.6% (n=1); occlusion within 30 days, 22.2% (n=4) Limb salvage rates at 6 and 12 months: 72.2% and 72.2% Overall survival rates at 6 and 12 months: 88.0% and 76.4% Amputation free survival rates at 6 and 12 months: 55.6% and 49.4% Freedom from MALE rates at 6 and 12 months: 55.6% and 50.0% Complete wound healing rates at 6 and 12 months, 23.0% and 53.2%; median time to complete wound healing, 234 days (IQR 127 to 306) | Major complication (compartment syndrome due to massive haematoma): n=1 fasciotomy and haematoma evacuation was needed for limb salvage. |
Cangiano (2021) | Technical success: 100% TcPO2: median number of measurements per patient, 12 (range 2 to 16)
Clinical improvement: 100%
Primary patency: median 8 months (range 3 to 12); In one patient, at 3-months follow-up presented occlusion of AVF that was successfully treated with venous thrombectomy. Minor amputation of 1 or more toes: 78.6% (11/14) Major amputations: n=3; limb salvage, 78.6% | MALE at 30 days: n=0 ST-elevation myocardial infarction (right coronary artery disease) after 2 weeks from PDVA: n=1 Death at 6 months: n=3, each unrelated to the procedure (1 patient died for a neurological complication after a fall in the ward, and 2 patients died for of pneumonia after 5 and 6 months from procedure). |
Del Giudice (2018) | Technical success: 100% with arterial-venous crossing, AVF creation and direct arterial flow to venous plantar arch. Mean procedure time: 248±45 minutes Mean fluoroscopy time: 76±15 minutes TcPO2: baseline, 10±2 mmHg; 4 weeks, 35±5 mmHg; 6 months, 43±4 mmHg; 12 months, 54±3 mmHg Immediate resolution of rest pain: 100% Clinical improvement: 60% (n=3); of whom 2 patients presented complete wound healing at 6 and 7 months, respectively. Primary patency at 6 months: 40% (n=2) Reintervention at 6 months: 60% (n=3) Major amputation at 6 months: 20% (n=1; a Rutherford 6 patient with extensive gangrene had a worsening of the clinical status with osteomyelitis at 6 months, despite the successful creation of the AF and a coiling reintervention of great saphenous collaterals.) | No major and minor complications or procedure-related death was reported in the periprocedural period. MACE at 6 and 12 months: 20% (n=1) SAE at 6 and 12 months: 80% (n=4) Death: n=1 from multiple organ failure due to a sepsis related to pneumonitis within 1 months after the procedure |
Kum (2017) | Technical success: 100%, with flow to the plantar venous arch achieved in 5 of 7 patients. Clinical improvement:
Complete wound healing:
Thermography was improved in all patients. Median time to loss of primary patency: 3.3 months (IQR 1.9 to 6.8) Reintervention to maintain patency: n=5, occlusions were addressed using percutaneous mechanical thrombectomy and drug-coated balloons to re-establish patency. Minor amputation of 1 or more toes: n=5 Major amputations within 12 months: n=2 (limb salvage, 71%) TcPO2:Median number of TcPO2 measurements per patients: 13 (IQR 4 to 17)
| MALE within 30 days: n=0, but 2 patients had medical treatment for non-ST-elevation MIs. Perioperative deaths associated with the procedure: n=0 Spontaneous retroperitoneal bleeding: n=1 at 8 weeks, probably from anticoagulation. Death at 12 months: n=3, unrelated to the device or procedure. Swelling: n=7 |
Procedure technique
All 6 studies detailed the procedure technique and devices used, although there was variation. In general, this procedure was done with ultrasound and fluoroscopic guidance, and using general anaesthesia, or local anaesthesia and conscious sedation. Once the location for arteriovenous connection was determined, the AVF was created either using a specific device (the LimFlow system) or using alternative techniques (VAST, modified VAST, arteriovenous spear technique, or the use of re-entry devices [such as OUTBACK, Pioneer Plus]). The arteriovenous connection was located at PTA-PTV, ATA-ATV, ATA-TPV, or PopA-PopV/PTV. Valvulotomy was performed using a dedicated valvulotome (from LimFlow) or a (cutting) balloon, and stents were deployed to reinforce the arteriovenous connection and to increase distal limb perfusion. Different types of stents were used. Angiography was done to visualise blood flow into the ischaemic tissue in the foot at the end of the procedure.
Efficacy
Technical or procedural success
Technical or procedural success was described in all 6 studies. The rate of technical success was 89% (16/18; Nakama 2022), 97% (31/32; Clair 2021; Schmidt 2020) and 100% (Kum 2017; Del Giudice 2018; Cangiano 2021). The rate of procedural success was 75% (24/32; Clair 2021).
Clinical improvement
Clinical improvement, including wound healing, was reported in all studies. Clair (2021) reported thatcore lab-adjudicated wound healing status of 'fully healed' or 'healing' was 67% (14/21) at 6 months and 75% (15/20) at 12 months. The authors also found that there was a decreasing mean WIfI score for each of the following 3 factors:
Mean wound scores: baseline, 1.81; 6 months, 0.81; 12 months, 0.74; 24 months, 0.42.
Mean ischaemia scores: baseline, 2.23; 6 months, 1.35; 12 months, 1.07; 24 months, 0.44.
Mean foot infection scores: baseline, 0.75; 6 months, 0.19; 12 months, 0.11; 24 months, 0.00.
Schmidt (2020) described that, of the 32 patients, the estimated rate of complete wound healing was 37% at 6 months, 68% at 12 months and 73% at 24 months. The median time to complete wound healing was 4.9 months (range 0.5 to15). Nakama (2022) reported that, of the 18 patients, complete wound healing rates were 23% at 6 months and 53% at 12 months, with a median time to complete wound healing of 234 days (IQR 127 to 306).
Cangiano (2021) reported clinical improvement in all 14 patients. The rate of complete wound healing was 64% (9/14) at 6 months and 79% (11/14) at 12 months, with a median healing time of 4.8 months. Del Giudice (2018) observed clinical improvement in 60% (3/5) of patients; of these, 2 patients had complete wound healing at 6 and 7 months, respectively. Kum (2017) described that clinical improvement was observed in all 7 patients with the formation of granulation; 2 of these patients had immediate resolution of rest pain. The authors also reported that the rate of complete wound healing was 57% (4/7) at 6 months and 71% (5/7) at 12 months, with a median healing time of 4.6 months (95% CI 84 to 192).
Tissue oxygenation assessed by TcPO2
TcPO2 values were presented in 4 studies. Schmidt (2020) reported that mean TcPO2 statistically significantly increased from 14.5±12.7 mmHg (n=13) at baseline to 56.1±11.9 mmHg (n=6) after 2 years. The authors stated that this became statistically significantly higher after 45 days (increase of 22.1 mmHg, p=0.027) and remained statistically significantly higher during follow up (increase of 41.7 mmHg, p<0.001) compared with baseline. Kum (2017) described that tissue perfusion was recorded in 6 of the 7 patients. Median TcPO2 values statistically significantly increased from 8 mmHg (IQR 3 to 27) before the procedure to 61 mmHg (IQR 50 to 76) after the procedure (p=0.046); in 5 of the 6 patients, a TcPO2 value of more than 40 mmHg was achieved.
Cangiano (2021) found that median TcPO2 increased from 8±2 mmHg (range 4 to 32 mmHg) at baseline to 56±4 mmHg (range 48 to 75 mmHg) at 6 months, with a TcPO2 value of 40 mmHg or more in 79% of the 14 patients. Del Giudice (2018) described that, of the 5 patients, TcPO2 increased from 10±2 mmHg at baseline to 35±5 mmHg at 4 weeks, 43±4 mmHg at 6 months, and 54±3 mmHg at 12 months.
Survival and AFS rates
Survival and AFS rates were reported in 3 studies. Clair (2021) reported that the AFS rate was 74% at 6 months and 70% at 12 months. Schmidt (2020) estimated that the AFS rate was 84% at 6 months, 71% at 12 months and 67% at 24 months. In addition, the authors reported that the overall survival rate was 94% at 6 months, 84% at 12 months and 80% at 24 months. Nakama (2022) described AFS rates of 56% at 6 months and 49% at 12 months. The authors also reported the overall survival rate was 88% and 76% at 6 and 12 months, respectively.
Limb salvage and amputations
Limb salvage or amputations were detailed in all 6 studies. Schmidt (2020) estimated the rate of limb salvage was 87%, 80% and 80% at 6, 12 and 24 months, respectively. Nakama (2022) reported a limb salvage rate of 72% at both 6 and 12 months, and a freedom from MALE rate of 56% at 6 months and 50% at 12 months. Kum (2017) found a limb salvage rate of 71% (5/7), with major amputations in 2 patients within 12 months and minor amputation of 1 or more toes in 5 patients. Cangiano (2021) reported a limb salvage rate of 79% (11/14) within 6 months, with major amputations in 3 patients. Del Giudice (2018) reported that major amputation was needed in 1 patient. Clair (2021) reported 19 minor amputations in 15 of the 32 patients, including 7 toe amputations, 2 ray amputations and 10 trans-metatarsal amputations.
Patency and reintervention
Patency and reintervention were described in 5 studies. Clair (2021) reported thatthe rate of reintervention was 52% (16/31), with 88% (14/16) of the maintenance reinterventions happening within the first 3 months. Most reinterventions (n=12; 75%) involved the arterial inflow tract proximal to the stented circuit, and no in-stent stenoses were determined to have been the cause of reintervention.
Schmidt (2020) reported DVA circuit occlusion in 21 patients, with a median of 2.6 months to occlusion. The authors also noted that 17 patients had reintervention for occlusion (16 because of unhealed wounds and 1 for a newly developed ulcer) and that 2 patients had reintervention for asymptomatic stenosis.
Cangiano (2021)described a median time of primary patency of about 8months (range 3 to 12), and 1 patient at 3 months follow up presented with occlusion of the AVF that was successfully treated with venous thrombectomy.
Del Giudice (2018) reported that primary patency remained in 2 patients and reintervention was done in 3 patients at 6 months.
Kum (2017)described that the median time to loss of primary patency was 3.3 months (IQR 1.9 to 6.8). The authors also reported that reintervention to maintain patency was done in 5 patients.
Safety
Mortality
Mortality was described in 4 studies. Schmidt (2020) reported death in 7 of the 32 patients because of progression of foot sepsis (n=1), a perforated diverticulum of the bowel despite laparotomy (n=1), myocardial infarction (n=2), pneumonia (n=2), and exacerbation of COPD (n=1). Cangiano (2021) reported death in 3 of the 14 patients at 6 months and these events were unrelated to the procedure. Del Giudice (2018) reported death in 1 of the 5 patients within 1 month after the procedure and this was caused by multiple organ failure because of sepsis related to pneumonitis. Kum (2017) reported death in 3 of the 7 patients at 12 months, but these events were unrelated to the device or procedure.
Myocardial infarction
Schmidt (2020) described that non-fatal myocardial infarction within 30 days was reported in 2 of the 32 patients. Cangiano (2021) reported that ST-elevation myocardial infarction (right coronary artery disease) was experienced in 1 of the 14 patients after 2 weeks from the procedure. Kum (2017) found that 2 of the 7 patients had medical treatment for non-ST-elevation myocardial infarction.
Major and severe adverse events
Nakama (2022) reported a major complication (compartment syndrome because of massive haematoma) in 1 patient who needed fasciotomy and haematoma evaluation for limb salvage. Del Giudice (2018) reported MACEs at 6 and 12 months in 1 patient (1/5) and SAEs at 6 and 12 months in 4 patients (4/5).
Other
Schmidt (2020) reported bleeding from a superficial vein adjacent to the granulating wound at 6 months (n=1), infection of the stent graft at 10 weeks (n=1), and a new wound on the forefoot at 8 months (n=1).
Kum (2017) described spontaneous retroperitoneal bleeding in 1 patient at 8 weeks (probably from anticoagulation) and some degree of swelling in all 7 patients.
Anecdotal and theoretical adverse events
Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).
They listed the following anecdotal and/or theoretical adverse events: pain, venous congestion, arterial injury, stent thrombosis, vessel dissection, distal embolisation, contrast nephropathy, and potential for high-output cardiac failure.
Six professional expert questionnaires for this procedure were received. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.
Validity and generalisability
Evidence came from both experimental and observational studies. The total sample size was small. No studies that were carried out in the UK were identified for inclusion in the key evidence. Two studies (Schmidt 2020; Nakama 2022) were retrospective, so recall bias was possible. The follow-up duration was short- to medium-term across studies.
Patients who had no-option CLTI were included. However, the term 'no-option CLTI' was not well, consistently defined across studies, resulting in several selection biases. It was suggested that no-option CLTI should be defined by quantitative evaluation (Nakama 2022).
Studies were conducted in difference countries, with some in multiple centres. There might be differences in treatment, such as provision of medical therapy and attentive wound care. It was acknowledged that a comprehensive multi-disciplinary approach to wound care is an essential aspect of the care pathways for this patient population. In addition, post-operational management (including wound care) is important but was only described in 2 studies (Clair 2021; Giudice 2020). Furthermore, there was variation in the procedure technique and devices used. Both the specific endovascular DVA system and ordinary ('off-the-shelf') devices were used for this procedure. It was also noted that this is a technically challenging procedure, particularly relating to AVF creation. This indicates that the experiences of individual operators in performing this procedure play an important role in the success of the treatment. However, operators' experiences were briefly mentioned in 2 studies only (Clair 2021; Schmidt 2020). All these factors ultimately affected the efficacy and safety outcomes.
None of the papers included in the key evidence reported that study was funded by a company. Declarations of interest were reported by 1 or more authors in 4 papers (Clair 2021; Schmidt 2020; Kum 2017; Nakama 2022).
Overall, evidence on the efficacy showed that the rate technical success ranged from 89% to 100%, the median time to complete wound healing ranged from 4.6 months to 7.8 months, and AFS rates ranged from 56% to 84% at 6 months, 49% to 71% at 12 months, and 67% at 24 months after the procedure. None of the studies reported quality of life outcomes.
The rates of technical success and AFS were lower, and time to wound healing was longer in Nakama (2022) than other studies included in the key evidence. Nakama (2022) argued that PDVA using alternative techniques and non-commercial-based devices (but not the LimFlow system) was performed, and this might have an impact on the key steps of AVF creation and valvulotomy. Also, patients with poorer background might affect the outcomes.
There are currently several ongoing trials, detailed below:
PROMISE International; NCT03321552; multiple centres, clinical trial (single group assignment, open-label); actual enrolment, n=35; estimated study completion date, January 2023.
The PROMISE II Trial, Percutaneous Deep Vein Arterialization for the Treatment of Late-Stage Chronic Limb-Threatening Ischemia (PROMISE); NCT03970538; multi-centre pivotal study (single group assignment, open label); estimated enrolment, n=120; estimated study completion date, February 2025.
PROMISE III: Percutaneous Deep Vein Arterialization for the Treatment of Late-Stage Chronic Limb-Threatening Ischemia; NCT05313165; clinical trial (single group assignment, open label); estimated enrolment, n=100; estimated study completion date, May 2027.
Percutaneous Deep Vein Arterialization Post-Market Study (PROMISE UK); NCT03807661; UK, clinical trial (single group assignment, open-label); estimated enrolment, n=25; estimated study complete date, July 2023.
Natural Progression of High-Risk Chronic Limb-Threatening Ischemia: The CLariTI Study; NCT04304105; US, observational cohort study (patient registry); actual enrolment, n=200; estimated study completion date, October 2023.
Despite these ongoing studies, in general there is a lack of control groups given "standard of care".
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