Abstract
Background
To evaluate the short-term clinical performance of Symvess (acellular tissue engineered vessel-tyod), formerly known as human acellular vessel, or HAV, compared with autologous vein for the treatment of extremity arterial injury.
Methods
Subjects treated with acellular tissue engineered vessel (ATEV) from two clinical trials were propensity score-matched on a 1:2 basis to PROspective Observational Vascular Injury Trial (PROOVIT) registry subjects with the same injured artery and treated with autologous vein. Matching characteristics included age, sex, trauma type (penetrating vs blunt), injury severity score, mangled extremity severity score, concomitant fracture, shunt use, and ischemia duration>6 hours. Incidence of outcomes (primary/secondary patency, amputation, conduit infection, reintervention for thrombosis/stenosis, pseudoaneurysm, and death) was assessed by a generalized linear model. Outcomes were assessed at Day 30 (ATEV group) or during initial hospitalization (autologous group).
Results
ATEV subjects lacking suitable autologous vein (n=67) and PROOVIT subjects treated with autologous vein (n=134) suffered injuries to axillary, brachial, femoral, popliteal, and posterior tibial arteries. Subgroups were clinically similar; Injury Severity Score, Mangled Extremity Severity Score, and duration of follow-up (16 vs 30 days) were higher for the ATEV subgroup.
Primary patency for the ATEV versus autologous group was 86.6% versus 91.8%, secondary patency: 91.0% versus 97.7%; amputation: 7.5% versus 8.2%; conduit infection: 1.5% versus 0%; reintervention for thrombosis or stenosis: 6.0% versus 8.2%; and death 4.5% versus 4.5%, respectively. No cases of pseudoaneurysm, true aneurysm, or significant differences between the ATEV and autologous groups for any outcome were observed.
Conclusions
Short-term outcomes were similar between ATEV subjects without feasible autologous vein, and propensity score-matched autologous vein recipients from the PROOVIT registry. The ATEV may provide effective and safe revascularization in subjects with extremity arterial injury without feasible autologous vein.
Level of evidence
Level 3, Therapeutic/Care Management
Keywords: extremities, Multiple Trauma, Vascular System Injuries
WHAT IS ALREADY KNOWN ON THIS TOPIC
It is well documented that extremity arterial injuries are universally contaminated and that the use of autologous vein for repair is associated with the best possible short- and long-term outcomes. However, innovation in this therapeutic area during the last several decades has failed to close the gap between non-autologous grafts and autologous vein with regards to patient-important outcomes (eg, patency rate, amputation rate, susceptibility to vascular conduit infection).
WHAT THIS STUDY ADDS
This study adds evidence regarding the performance of a recently US Food and Drug Administration-approved, first-of-its-kind acellular tissue-engineered vessel (ATEV) in extremity arterial injury compared with a same-artery and propensity score-matched group of patients treated with autologous vein. Despite being underpowered, the study evaluated the largest possible sample size of patients available today, and showed no significant differences in outcomes between autologous vein and ATEV.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study provides clinicians and healthcare decision-makers (such as hospital value analysis committees) with the best available comparative evidence of the performance of a new technology versus the gold standard in extremity arterial injury, and may result in use of the new technology in lieu of non-autologous graft options. It is expected that future real-world studies will generate evidence to support the effectiveness of the new technology.
Introduction
For subjects with extremity arterial injury, autologous saphenous vein is the gold standard due to its favorable patency outcomes, infection resistance, and low amputation rates. One study of long-term outcomes1 showed that vein more than doubles the rate of freedom from graft-related complications at 8 years.1,3 Current guidelines for treatment of peripheral vascular injuries4 state that although vein is the conduit of choice, prosthetic grafts may be used when vein is not available or not suitable. However, lack of alternate, US Food and Drug Administration (FDA)-approved, vascular treatment options means that when autologous vein is not available, surgeons have few good options, beyond prosthetic grafts, for repair of extremity arterial injuries.5
Symvess (acellular tissue-engineered vessel-tyod), also known as ATEV (formerly known as human acellular vessel, or HAV), received FDA approval in December 2024 and represents an important technological and therapeutic development for the treatment of extremity arterial injury.6,9 The ATEV has been described previously, and is a bioengineered human vascular tissue, 6 mm in diameter and 40 cm in usable length, that is grown from human vascular cells.9,16 After the growth of the engineered artery, the vessel is decellularized, leaving behind an acellular human, tubular extracellular matrix.9 This matrix is conducive to repopulation by various types of cells from the recipient, which transform the ATEV into a living vessel with a structure and histology mimicking that of a human artery (figure 1).9
Figure 1. (A) Representation of histological remodeling process for ATEV. Left panel: H&E of ATEV prior to implantation. Right panel: H&E shows repopulation of ATEV after 44 weeks of implantation as arteriovenous access for hemodialysis. (B) Illustration of the remodeling process observed from clinical explant specimens. ATEV, acellular tissue engineered vessel; HAV, human acellular vessel.
Outcomes have been reported for the ATEV when used to treat traumatic injuries of the extremities.10 11 17 These outcomes are from civilian subjects in a single-arm prospective clinical study,10 17 as well as from subjects suffering from wartime injuries in Ukraine in a retrospective clinical study.11 All ATEV-treated subjects were deemed by operating surgeons as having no suitable autologous vein for arterial repair. Outcomes for the ATEV were previously compared with historical benchmarks of prosthetic graft performance in arterial trauma, based on a systematic review and meta-analysis of published medical literature from 2002 to 2023.17,19 This analysis found important clinical differences favoring the ATEV, particularly for conduit infections (0.9% vs 8.4%), amputations (4.5% vs 23.4%), and secondary patency (91.5% vs 78.9%), with the ATEV performing better than prosthetic grafts for each of these outcomes.17,19 However, no prior comparison between ATEV and autologous vein exists.
This study used the PROspective Observational Vascular Injury Trial (PROOVIT) registry as a source of historical comparator data for the ATEV in extremity arterial injury.20 PROOVIT is the world’s largest database of vascular injury subjects, comprising more than 5,000 subjects treated to date at level I/II trauma centers in the USA. Subjects in PROOVIT who received vein for arterial injury repair were propensity score-matched to subjects who received the ATEV for injury repair. Assessment of primary patency of the venous conduit, amputation of the treated limb, and conduit infection were taken from data elements within the PROOVIT database. This report contains ATEV treatment outcomes compared with outcomes resulting from autologous vein treatment in propensity-matched PROOVIT subjects. The hypothesis of this study is that there are no significant differences in early outcomes after extremity arterial repair, including patency, amputation, or infection rate between autologous vein and the ATEV among propensity-matched subjects with extremity arterial injury.
Methods
Data sources and comparison groups
V005 Arterial injury clinical trial – prospective controlled trial
The CLN-PRO-V005 clinical trial (NCT03005418) is a prospective, multicenter, single-arm study conducted in the USA and Israel in adult trauma subjects with arterial injuries resulting from gun shots, workplace injuries, car accidents, or other traumatic events. V005 enrolled 69 subjects between September 1, 2018, and June 30, 2023, of which 51 suffered non-iatrogenic extremity arterial injuries, as prespecified in the clinical trial protocol.17 21 22 Inclusion criteria were extremity arterial injury in adults aged 18–85, with defect length≤38 cm, and life expectancy of at least 1 year. Exclusion criteria were Mangled Extremity Severity Score (MESS)≥7, Injury Severity Score (ISS)≥60, and a contraindication to antiplatelet medications. All subjects underwent arterial repair with ATEV. Subjects were recommended to receive antiplatelet medication postoperatively, either aspirin or an alternative, at the discretion of the investigator. The primary efficacy endpoint of V005 was primary patency of the ATEV at Day 30 after implantation.21 Patency was assessed by physical examination and/or ultrasound or angiographic imaging. Primary patency was defined as the ATEV maintaining functional patency without any type of required intervention. Secondary efficacy endpoints included secondary patency, conduit infection, amputation of the treated limb, and patient survival.21 Secondary patency was assessed by physical examination and imaging, and was defined as functional patency of the ATEV, regardless of any preceding interventional or surgical procedures to maintain or re-establish patency, until final failure or abandonment of the ATEV. Subjects who remain on study are followed for up to 36 months after ATEV implantation, and follow-up is ongoing.
V017 Humanitarian real-world clinical trial – retrospective study
In June 2022, ATEVs were provided to five hospitals in Ukraine for the treatment of war-wounded soldiers under a humanitarian effort that was approved by the International Office at the FDA.11 19 subjects were treated during a 1-year period under this humanitarian effort. The CLN-PRO-V017 clinical trial was designed to collect retrospective data on subjects treated under this program (NCT05873950). Inclusion and exclusion criteria for V017 mirrored those of V005. 17 of 19 subjects participated in data collection, of which 16 had non-iatrogenic extremity injuries.11 23 The V017 outcomes, data collection, and endpoints mirrored those in the V005 study. As in V005, in V017 the ATEV patency was assessed by physical examination and/or ultrasound or angiographic imaging.
For both V005 and V017, data elements were collected for demographics (age, sex, race/ethnicity), named injured artery, type of trauma (blunt vs penetrating), ISS, MESS, initial surgery characteristics/observations (ie, shunt use, ischemia time>6 hours, concomitant orthopedic fracture), and study endpoints (ie, primary/secondary patency, amputation, conduit infection, reintervention for thrombosis/stenosis, aneurysm, pseudoaneurysm, and death).
The endpoint assessment for the ATEV studies occurred at Day 30. For subjects who suffered an intercurrent event such as death or amputation prior to Day 30 that prevented assessment of patency, the event was independently adjudicated for whether the ATEV was patent at the time of the event, and whether the event was caused by the ATEV. In cases where the ATEV was deemed as causative, the ATEV was counted as not patent. In cases where the event was not caused by the ATEV, and where there was assessment of ATEV patency prior to the event, then the patency status was carried forward to Day 30 using a while-on-treatment approach.12 Loss of the treated limb, or amputation, was counted only when an amputation actually occurred, and not simply when a patient died due to concomitant injuries or was lost to follow-up. In terms of subjects who had a scheduled Day 30 visit, 37/51 subjects in the V005 study and 16/16 subjects in V017 had Day 30 visits, for a combined 53/67 subjects with data collected from a scheduled Day 30 visit.
The subjects suffering non-iatrogenic extremity arterial injury in V005 and V017 (51 and 16 subjects, respectively) had similar ages (33.5 and 34.2 years). The majority suffered penetrating trauma (56.9% and 87.5%), and there was a preponderance of lower extremity injuries (80.4% and 87.5%) in V005 and V017, respectively. ISS scores were similar in V005 and V017 (20.8 and 20.1), indicating serious traumatic injury. Given the similarities of the patient and injury characteristics, data for ATEV outcomes from V005 and V017 were combined for this comparison to civilian autologous vein outcomes in PROOVIT.
PROOVIT registry
PROOVIT is a vascular trauma registry sponsored by the American Association for the Surgery of Trauma Multicenter Trials Committee and has been described in detail in previous publications.20 The registry, initiated in 2013, is the largest repository of vascular trauma data in the USA and includes elements of vascular trauma presentation, diagnosis, management during the initial episode of care, and outcomes from different level I/II trauma centers in the USA. As of November 2023, PROOVIT had collected data from 5,463 subjects with vascular injuries, of whom 5,222 were adults. In most cases, data elements within PROOVIT are similar to the data elements that were captured for the ATEV studies V005 and V017, thereby allowing for the matching of subjects based on similar demographic, clinical, and baseline characteristics.
Propensity score matching
For analysis of the PROOVIT dataset, all propensity score matching of ATEV subjects to autologous vein subjects was performed by Fortrea Clinical Research Organization, including the evaluation of multiple matching algorithms to identify the method resulting in highest-quality matching outcomes.
For the propensity matching process, subjects were initially matched by type of artery that was injured: axillary, brachial, femoral (including common, superficial, and deep), popliteal, or posterior tibial. The PROOVIT data did not distinguish common and superficial femoral arteries; hence, ATEV subjects with an injury to either the common or superficial femoral arteries were categorized into a single group. Additionally, there were 16 PROOVIT subjects with injuries to two arteries. For purposes of matching and analysis, the more proximal injury was chosen as the artery of interest when the arteries perfused the same territory. Both arteries were eligible to be matched when the arteries were not connected (ie, perfusing different limbs). To maintain consistency with how outcomes are evaluated in the PROOVIT registry, outcomes were assessed at the injured artery level, not at the patient level.
After matching for artery injured, subjects from the ATEV and PROOVIT autologous groups were then matched by propensity scores, using a nearest neighbor greedy algorithm without replacement.24 Characteristics used for matching were: age, sex, ISS, MESS, total ischemia time (≤6 hours, >6 hours), type of injury (penetrating vs blunt), shunt use, and concomitant orthopedic fracture. Three different matching approaches were considered: (1) 1:1 matching: each ATEV patient was matched to an autologous group patient having the closest propensity scores at the time of matching; (2) 1:2 matching by selecting one ATEV patient to two autologous group subjects having the closest propensity scores in one matching cycle; and (3) 1:2 matching by selecting one ATEV patient to two autologous group subjects in two cycles: each ATEV patient was first matched to one autologous group patient, and then the process was repeated for a second cycle with the remaining autologous group subjects who were not matched in the first cycle. Overall propensity matching scores were then compared between the three approaches to identify the most robust matching algorithm. Patient population balance achieved by propensity score matching was assessed using absolute standardized differences, with meaningful imbalances defined as an absolute standardized difference>0.2.
Missing values were observed for ISS and MESS in both the ATEV and autologous groups; all other variables in this analysis did not have any missing data. ISS was missing for two patients from the ATEV group, and MESS was missing for six patients from the ATEV group. For the PROOVIT autologous group, ISS was missing for 10 subjects, and MESS was missing for 18 subjects meeting all inclusion/exclusion criteria to be considered for potential matching. When ISS and MESS scores were missing, values were imputed based on the means of the subjects within each group.
Analysis
Clinical outcomes of interest for ATEV and autologous subjects
The outcomes of primary and secondary patency of the conduit, amputation of the treated limb, vascular conduit infection (as distinct from localized wound infection), reintervention to treat a thrombus/stenosis, pseudoaneurysm or aneurysm, and death were compared between the ATEV and autologous vein study arms. Comparisons were made at Day 30 for the ATEV group, and at the completion of initial hospitalization for the PROOVIT autologous vein group. Time-to-event information was not available for either the ATEV or the autologous group, only the occurrence of events during the aforementioned observation periods. Patency data were available for the ATEV group, since patency was an outcome of the studies and was assessed by physical examination and/or clinical imaging. For the autologous group, primary patency was defined as the occurrence of any reintervention for any of the PROOVIT-specified events that indicate a loss of primary patency and included: “thrombosis of definitive vascular repair, treatment of spontaneous rupture, occlusion, flow limiting stenosis of vascular repair, pseudoaneurysm of vascular repair, aneurysm formation, or infection resulting in need to re-operate”. Secondary patency was defined as an affirmative response to the query, “Was patency restored with repeat intervention?”.
All other outcome variables for both the ATEV and the autologous vein groups were available without transformation or imputation. ATEV outcomes of patency, limb salvage, and conduit infection were explicitly collected during the trial. For the PROOVIT autologous vein data, in the absence of data elements to the contrary, veins were ascribed as patent, limb salvage ascribed as successful, and vein conduits were ascribed as infection-free.
Analysis of incidence rates
Using an integrative data analysis approach,25 the analysis examined the differences in the incidence rates of the various outcomes between the ATEV group and autologous group. The incidence rate and rate difference for each outcome were calculated using a generalized linear model, assuming a binomial distribution and a log link function.26 In the event where the regression statistical models did not converge, descriptive results were implemented using Fisher’s exact test.27
Power analysis
At the time of this analysis, the sample size available was underpowered for a non-inferiority study, as this would have required at least 230 subjects per group (see online supplemental table 1). Despite this limitation, we provide the results of this analysis with all the available data from clinical trials and a well-matched cohort.
Results
The two-cycle, 1:2 matching method was selected to evaluate the endpoints of interest, as it matched 100% of ATEV subjects to two subjects treated with saphenous vein in PROOVIT and showed superior balance across all variables, as evidenced by a greater number of variables with standardized difference value<0.2 as compared with the one-cycle 1:2 matching method (seven out of nine variables balanced vs six out of nine, respectively). All data shown below are derived from the 1:2 (two-cycle) matching method.
Patient totals and patient capture for analysis in this study are shown in table 1. Overall, there were 67 ATEV subjects and 452 adult PROOVIT subjects having extremity arterial injury who were available for analysis and propensity matching. All of the ATEV subjects suffering non-iatrogenic arterial injury of the extremities as of the data cut-off of June 30, 2023, were included. Of the PROOVIT autologous subjects, 452 subjects represent 10.2% of the entire PROOVIT population over the age of 18 years and having complete records.
Table 1. Patient capture from ATEV trials and PROOVIT registry.
| Criteria | N (%) |
|---|---|
| ATEV subjects – V005 trial | |
| V005 trial subjects with non-iatrogenic injury to an extremity | 51 |
| ATEV subjects – V017 trial | |
| V017 trial subjects with non-iatrogenic injury to an extremity | 16 |
| Total ATEV subjects with non-iatrogenic injury to an extremity | 67 |
| PROOVIT subjects | |
| All PROOVIT subjects | 5,463 |
| Status = “Complete” (ie, record complete) | 4,639 (84.9) |
| ≥18 years old | 4,419 (80.9) |
| Autologous vein interposition or bypass graft repair to: axillary, brachial, femoral, popliteal, or posterior tibial arteries | 452 (10.2) |
| Final PROOVIT population | 452 (10.2% of complete, ≥18 years old subjects) |
ATEV, acellular tissue engineered vessel; PROOVIT, The PROspective Observational Vascular Injury Trial.
Patient demographics
Patient demographics before and after matching are shown in table 2.
Table 2. Demographics and baseline injury characteristics before and after matching.
| Demographic | Before propensity score matching | After matching | |||
|---|---|---|---|---|---|
| ATEV group (N=67) |
Autologous group (N=452)* |
Absolute standardized difference (ATEV vs autologous group) |
Autologous group (N=134) |
Absolute standardized difference | |
| Days of follow-up mean (SD) | 30 | 12.6 (11.2) | 2.19 | 16.0 (13.19) | 1.50 |
| Artery | 0.49 | 0.00 | |||
| Axillary artery | 2 (3.0%) | 23 (5.1%) | 4 (3.0%) | ||
| Brachial artery | 10 (14.9%) | 151 (33.2%) | 20 (14.9%) | ||
| Femoral artery | 29 (43.3%) | 123 (27.0%) | 58 (43.3%) | ||
| Popliteal artery | 25 (37.3%) | 148 (32.5%) | 50 (37.3%) | ||
| Posterior tibial artery | 1 (1.5%) | 10 (2.2%) | 2 (1.5%) | ||
| Age at index | 0.04 | 0.05 | |||
| Mean (SD) | 33.7 (12.62) | 33.2 (12.77) | 33.1 (12.22) | ||
| Median | 30.0 | 29.0 | 30.5 | ||
| Sex, n (%) | 0.16 | 0.12 | |||
| Male | 54 (80.6) | 394 (86.6) | 114 (85.1) | ||
| Type of trauma | 0.25 | 0.19 | |||
| Blunt | 24 (35.8%) | 153 (33.6%) | 40 (29.9%) | ||
| Penetrating | 43 (64.2%) | 287 (63.1%) | 93 (69.4%) | ||
| Mixed blunt and penetrating | 0 | 15 (3.3%) | 1 (0.7%) | ||
| ISS† | 0.62 | 0.29 | |||
| Mean (SD) | 20.6 (12.17) | 14.0 (8.63) | 17.3 (10.46) | ||
| Median | 17.0 | 11.0 | 16.0 | ||
| MESS‡ | 0.40 | 0.27 | |||
| Mean (SD) | 5.1 (1.57) | 4.5 (1.68) | 4.7 (1.61) | ||
| Median | 5.0 | 4.5 | 4.5 | ||
| Fracture, n (%) | 46 (68.7) | 180 (39.6) | 0.61 | 85 (63.4) | 0.11 |
| Shunt, n (%) | 17 (25.4) | 43 (9.5) | 0.43 | 29 (21.6) | 0.09 |
| Ischemia time>6 hours, n (%) | 3 (4.5) | 52 (11.4) | 0.26 | 4 (3.0) | 0.08 |
Bold text is used to orient the reader to the standardized difference numbers.
Three PROOVIT subjects each had repair to two arteries of interest.
Missing ISS scores were imputed with the mean value of all non-missing ISS scores from subjects within each individual study arm.
Missing MESS scores were imputed with the mean value of all non-missing MESS scores from subjects within each individual study arm.
ATEV, acellular tissue engineered vessel; ISS, Injury Severity Score; MESS, Mangled Extremity Severity Score; n, number of subjects; PROOVIT, The PROspective Observational Vascular Injury Trial; SD, standard deviation.
All ATEV subjects (n=67) were matched on a 1:2 basis with two autologous subjects (n=134) with an injury to the same artery. No patients with more than one artery affected were included in this analysis. After matching, all variables were well balanced with standardized differences of<0.2, except for length of stay (longer in ATEV group), ISS (higher in ATEV group), and MESS (higher in ATEV group) (table 2). Length of stay/length of follow-up differs between ATEV subjects and PROOVIT subjects because ATEV patient data were uniformly collected at Day 30, whereas PROOVIT data were limited to the initial hospital stay, which was typically less than 30 days (average length of stay: 16 days).
Greater injury severity in the ATEV subjects is evident in the overall higher ISS and MESS scores. Aside from length of stay, ISS, and MESS, other variables on clinical and demographic characteristics were closely matched. The two cohorts were well matched on age, sex, presence of concomitant fracture, use of temporary vascular shunts, mechanism of trauma (blunt vs penetrating), and ischemia time.
Outcomes
Overall, outcomes were similar across the ATEV group and the autologous group (table 3). There were no statistically significant differences in primary patency (p=0.28), secondary patency (p=0.08), amputations (p=0.85), conduit infection (p=0.33), death (p=0.99), or reinterventions for thrombosis or stenosis (p=0.55). There were also no cases of pseudoaneurysm or aneurysm in either the ATEV or the autologous group (table 3).
Table 3. Comparison of ATEV outcomes to autologous group outcomes.
| Outcome | ATEV group incidence rate (%, 95% CI) |
Autologous group incidence rate (%, 95% CI) |
Autologous – ATEV rate difference (%, 95% CI) |
P value |
|---|---|---|---|---|
| Primary patency | 86.6 (78.8 to 95.1) |
91.8 (87.3 to 96. 6) |
5.2 (−14.6 to 4.2) |
0.28 |
| Secondary patency | 91.0 (84.5 to 98.1) |
97.7 (95.1 to 100.3) |
6.6 (−13.9 to 0.7) |
0.08 |
| Amputation | 7.5 (3.2 to 17.3) |
8.2 (4.7 to 14.5) |
0.8 (−8.6 to 7.1) |
0.85 |
| Conduit infection* | 1.5 | 0 | −1.5 | 0.33 |
| Death | 4.5 (1.5 to 13.5) |
4.5 (2.1 to 9.9) |
−0.03 (−6.1 to 6.1) |
0.99 |
| Reintervention for thrombus/stenosis | 6.0 (2.3 to 15.4) |
8.2 (4.7 to 14.5) |
2.2 (−9.6 to 5.1) |
0.55 |
| Pseudoaneurysm | 0 | 0 | N/A | N/A |
| Aneurysm | 0 | 0 | N/A | N/A |
Comparison conducted using Fisher’s exact test due to regression not converging.
ATEV, acellular tissue engineered vessel; CI, confidence interval; N/A, not applicable.
Analyses of outcomes by vessel type also found no significant differences in secondary patency, infection, or limb salvage between the ATEV and autologous vein treatments. For lower extremity vasculature (table 4), repair of the femoral artery resulted in 100.0% secondary patency for autologous vein, and 96.6% for ATEV. Limb salvage was 96.6% for autologous vein and 100.0% for ATEV. There were no documented infections in either group at 30 days. Similarly, popliteal/tibial outcomes between the ATEV and autologous vein groups were not statistically different. Secondary patency was 94.1% with autologous vein, and 88.5%, with ATEV (p=0.40). Popliteal/tibial artery repair infections were 0% with autologous vein and 3.8% with ATEV (p=0.33), and limb salvage was 86.5% with autologous vein, and 80.8% with ATEV (p=0.52). Comparison of outcomes for the repair of upper extremity vasculature (axillary and brachial arteries) also found no differences between the groups (table 5). Postoperative anticoagulation or antiplatelet therapy was used in 96.3% of PROOVIT patients and 85.1% of ATEV patients (p=0.001; data not shown).
Table 4. Comparison of ATEV outcomes to autologous group outcomes, lower extremities.
| Lower limb | Outcome | ATEV incidence rate (%, 95% CI) |
Autologous group incidence rate (%, 95% CI) |
Autologous – ATEV rate difference (%, 95% CI) |
P value |
|---|---|---|---|---|---|
| Femoral | N=29 | N = 58 | |||
| Secondary patency | 96.6 (82.2 to 99.9) |
100.0 (93.5 to 100.0) |
3.4 (−3.7 to 17.9) |
0.35 | |
| Infection | 0.0 (0.0 to 11.9) |
0 (0.0 to 6.2) |
N/A | N/A | |
| Limb salvage | 100.0 (88.1 to 100.0) |
96.6 (88.1 to 99.6) |
−3.4 (−12.2 to 9.4) |
0.55 | |
| Popliteal/tibial | N=26 | N = 52 | |||
| Secondary patency | 88.5 (69.9 to 97.6) |
94.1 (83.8 to 98.8) |
5.7 (−7.8 to 24.6) |
0.40 | |
| Infection | 3.8 (0.1 to 19.7) |
0 (0.0 to 6.9) |
−3.8 (−19.7 to 3.6) |
0.33 | |
| Limb salvage | 80.8 (60.7 to 93.5) |
86.5 (74.2 to 94.4) |
5.8 (−11.2 to 26.6) |
0.52 |
Risk and risk difference are calculated using a generalized linear model assuming a binomial distribution and a log link function.
P value calculated from Fisher’s exact test.
ATEV, acellular tissue engineered vessel; CI, confidence interval; N/A, not applicable.;
Table 5. Comparison of ATEV outcomes to autologous group outcomes, upper extremities.
| Upper limb | Outcome | ATEV incidence rate (%, 95% CI) |
Autologous group incidence rate (%, 95% CI) |
Autologous – ATEV rate difference (%, 95% CI) |
P value* |
|---|---|---|---|---|---|
| Axillary/brachial | N=12 | N = 24 | |||
| Secondary patency | 83.3 (51.6 to 97.9) |
100.0 (84.6 to 100.0) |
16.7 (−2.5 to 48.4) |
0.12 | |
| Infection | 0.0 (0.0 to 26.5) |
0 (0.0 to 14.3) |
N/A | N/A | |
| Limb salvage | 100.0 (73.5 to 100.0) |
91.7 (73.0 to 99.0) |
−8.3, (−27.3 to 18.2) |
0.543 |
Risk and risk difference are calculated using a generalized linear model assuming a binomial distribution and a log link function.
P value calculated from Fisher’s exact test.
ATEV, acellular tissue engineered vessel; N/A, not applicable.
Discussion
In support of our initial hypothesis, we did not find any significant differences between the ATEV and autologous vein groups, although this does not demonstrate non-inferiority due to the limited sample size of the two populations. A power analysis conducted prior to this propensity score-matched analysis indicated that a non-inferiority study comparing ATEV to saphenous vein would require sample sizes approximately three times larger than what were available for the present analysis. Although underpowered, this analysis evaluated the two largest available groups of patients with extremity arterial injury treated with either autologous vein or ATEV. Recruitment for the ATEV clinical studies occurred during a 6-year period, and yet less than 70 subjects were recruited due to the challenges inherent in recruitment of patients with traumatic injuries. Nevertheless, the availability of rigorous and prospectively collected clinical trial data for a population treated with ATEV provides an opportunity to gain an early understanding of the comparative effectiveness in this therapeutic area. However, these early insights must be tempered by the acknowledgement that the sample sizes are small, and additional longer-term data collected in larger numbers of patients would be required for a more definitive comparison.
Despite the low sample size, this analysis provides some evidence of the effectiveness and safety of ATEV relative to autologous vein, which is the gold standard in extremity arterial injury. Prospective studies of traumatic injuries to named arteries are very challenging to perform. Indeed, to the best of our knowledge, no prospective, randomized head-to-head trial has ever been conducted evaluating two surgical care options for named arterial injuries.
Sources of imbalance between the ATEV and autologous vein groups should be noted. Evaluation of outcomes occurred at Day 30 for the ATEV group, whereas for the autologous group, the mean length of stay was 16.0 days, suggesting that the observed frequency of outcomes may be biased against the ATEV group. This is a limitation related to how different studies collected data. Another slight bias against the ATEV is somewhat lower ISS and MESS scores for autologous subjects as compared with ATEV subjects, indicating a lower severity of trauma in the propensity-matched autologous subjects from PROOVIT. The impact of imputation in the ATEV group is expected to be de minimus, since only a small fraction of the ATEV patients had missing values (~10%). For the PROOVIT autologous group, approximately 20% of patients had a missing ISS or MESS score. Not imputing ISS and MESS would have led to a loss of sample size, as no propensity score could be calculated on observations with missing values for any of the match variables, and a missed opportunity to match on the only variables common to both datasets that provided an estimate on the severity of the injury. In addition, since matching was performed on a range of factors in addition to ISS/MESS, the quality of the matching is not expected to be impacted by missing values in the PROOVIT group.
Though bias can never be completely avoided, an effort to adjust for confounding variables was made by first matching ATEV patients with autologous patients based on the same injured artery, and subsequently through the use of propensity score matching. Furthermore, analysis via generalized linear model further limited bias from measured variables. The short-term outcomes in this study were evaluated only during the initial hospitalization for autologous group patients, ensuring high rates of compliance with antiplatelet therapy, as it would be administered by hospital staff. For ATEV patients, outcomes were recorded at Day 30, a period of time during which high compliance with antiplatelet therapy would also be expected. Although prevalent in both groups, the significantly higher use of anticoagulation/antiplatelets in the autologous group may have improved patency rates for that cohort. Lastly, bias from unmeasured variables cannot be ruled out.
Arterial injury of the extremities carries a high risk of infection due to its inherently contaminated nature28 29 and a high risk of amputation that is related to trauma severity and ischemia time, among other factors.30 Infection and amputation risk have been shown to be lower with saphenous vein as compared with prosthetic grafts.5,8 However, an analysis of PROOVIT data has shown that use of saphenous vein is not feasible in approximately 20-25% of subjects with extremity arterial injury and, therefore, use of a prosthetic or other type of graft is required.31 Both patency and limb salvage, as well as long-term outcomes, are markedly inferior with prosthetic grafting.13 4 32,34
In this analysis, the rate of infection was low in both the ATEV and autologous vein groups. The PROOVIT registry only captures infections associated with the definitive management choice during the initial hospitalization. The absence of conduit infections among 134 autologous group patients, although impressive, is not unexpected, as recent analysis of the PROOVIT registry showed that there were only five conduit infections among 470 patients (1.06%) who received autologous vein for extremity arterial injury.31 In the ATEV population, there were a total of 10 surgical infections within 30 days, but only one case of ATEV infection among 67 patients within the same time period (1.5%). This may indicate that the ATEV’s biocompatibility with the host’s cells allows for protection against infection of the vascular conduit.
The ATEV has accumulated more than 1200 patient-years of experience worldwide in a series of clinical trials in multiple indications, including extremity arterial injury repair, arteriovenous access for hemodialysis, and peripheral artery disease.12,16 The ATEV has been studied in the care of arterial injury subjects since 2016.21 In extremity arterial injury, long-term outcomes for ATEV of up to 3 years post-injury for secondary patency, limb salvage, and freedom from conduit infection have been reported17 and are reassuring. The ATEV is mechanically durable and does not appear to dilate or become stenotic over time, as assessed by mid-graft diameters by duplex ultrasonography up to 36 months.17
The ATEV is stored in refrigerated conditions and can be available to the surgeon almost immediately, since it does not require thawing or rinsing. This immediate availability, without the need to spend time harvesting autologous vein, may speed revascularization in subjects suffering extremity traumatic injuries. With similar short-term clinical outcomes to autologous vein, the ATEV may represent an important addition to the treatment options for extremity arterial injury repair in acute trauma, especially in patients who have no feasible autologous vein available.
Conclusion
Study findings suggest that important clinical outcomes (ie, patency, amputation, conduit infection, reintervention, aneurysm/pseudoaneurysm, and death) appeared to be similar for ATEV as compared with autologous vein external controls from the PROOVIT registry. These findings further support the use of the bioengineered ATEV for arterial injury repair in the extremities.
Supplementary material
Acknowledgements
The authors thank Natalie Edwards of Health Services Consulting Corporation, Boxborough, Massachusetts, USA, for editorial assistance with the manuscript. The authors thank Maria Fadri of Humacyte, Durham, North Carolina, USA, for manuscript and figure revision.
Footnotes
Funding: The study was funded by Humacyte.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: IRB and Ethics committee approvals were obtained prior to data collection under the V005 and V017 protocols. This current study, comparing outcomes of V005/V017 to PROOVIT, was exempt from IRB approval as this research analyzed data from previously conducted clinical trials and an anonymous, de-identified, clinical registry (PROOVIT database) that is compliant with the Health Insurance Portability and Accountability Act of 1996.
Data availability free text: PROOVIT and ATEV clinical trial data are not publicly available.
Data availability statement
Data may be obtained from a third party and are not publicly available.
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Associated Data
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Supplementary Materials
Data Availability Statement
Data may be obtained from a third party and are not publicly available.