PuraStat®; Post Market Performance during Vascular Surgery
Research type
Research Study
Full title
A Multi-center, Single Arm Post-market Clinical Study to Confirm Safety and Performance of PuraStat® Absorbable Haemostatic Material for the Management of Bleeding In Vascular Surgery
IRAS ID
217324
Contact name
Carole Robin
Contact email
Sponsor organisation
3-D Matrix Europe SAS
Duration of Study in the UK
0 years, 10 months, 31 days
Research summary
The study is a multi-centre, post-market clinical study to confirm the safety and performance of PuraStat®, an absorbable haemostatic material used for the management of bleeding during vascular surgery.
The study will primarily assess "time-to-haemostasis" after the application of PuraStat® in patients undergoing elective carotid endarterectomy. In addition, the study will continue to assess the safety profile of this already CE-marked haemostatic material.
Up to 65 patients, clinically indicated for elective carotid endarterectomy will be invited to participate in the study.
It is anticipated that up to 6 hospitals across Europe, including 2 NHS Hospitals in the UK, will participate and that patient recruitment will be completed within 5 months.
Lay Summary of Results
Abstract
Anastomotic bleeding in vascular surgery can be difficult to control. Patients, in particular those undergoing carotid surgery, have
often been started on treatment with dual antiplatelet agents and receive systemic heparinization intraoperatively. The use of
local hemostatic agents as an adjunct to conventional methods is widely reported. 3-D Matrix’s absorbable hemostatic material
RADA16 (PuraStat®), is a fully synthetic resorbable hemostatic agent. The aim of this study is to confirm the safety and performance
of this agent when used to control intraoperative anastomotic bleeding during carotid endarterectomy (CEA). A prospective,
single-arm, multicenter study involving 65 patients, undergoing CEA, in whom the hemostatic agent was applied to the
suture line after removal of arterial clamps. Patients were followed up at 24 h, discharge, and one month after surgery. Time
to hemostasis was measured as the primary endpoint. Secondary endpoints included hemostasis efficacy and safety outcomes,
blood loss, intraoperative and postoperative administration of blood products, and incidence of reoperation for bleeding. A
total of 65 cases (51 male and 14 female) undergoing CEA, utilizing patch reconstruction (90. 8%), eversion technique
(6.1%), and direct closure (3.1%) were analyzed. All patients received dual antiplatelet therapy preoperatively and were administered
systemic intravenous heparin intraoperatively, as per local protocol. The mean time to hemostasis was 83 s±105 s (95%
CI: 55-110 s). Primary hemostatic efficacy was 90.8%. The mean volume of product used was 1.7 mL±1.1 mL. Hemostasis was
achieved with a single application of the product in 49 patients (75.3%). Two patients required a transfusion of blood products
intraoperatively. There were no blood product transfusions during the postoperative period. The intraoperative mean blood loss
was 127 mL ±111.4 mL and postoperatively, the total mean drainage volume was 49.0 mL±51.2 mL. The mean duration of surgery
was 119±35 min, and the mean clamp time was 35 min 12 s±19 min 59 s. In 90.8% of patients, there was no presence of
hematoma at 24 h postoperatively. Three returned to theatre due to bleeding (2 in the first 24 h), however, none of these cases
were considered product related. Overall, there were no device-related serious adverse events (SAE) or unanticipated devicerelated
SAEs reported. Use of the hemostatic agent PuraStat® is associated with a high rate of hemostatic efficacy (90.8%) and a
short time to hemostasis. The safety of the product for use on vascular anastomoses has been demonstrated.
Keywords
hemostasis, self-assembling peptides, RADA16, vascular surgery, carotid endarterectomy, case series
Date received: 7 July 2022; revised: 10 November 2022; accepted: 23 November 2022.
1 St George’s Vascular Institute, St George’s Hospital, London, UK
2 St George’s University of London, Cranmer Terrace, London, UK
3 Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
4 Department of Vascular Surgery, University Hospitals Leuven, Leuven, Belgium
5 Vascular Surgery Unit, York Teaching Hospital NHS Foundation Trust, York, North Yorkshire, UK
6 Department of Vascular Surgery, St Mary’s Hospital, Imperial College London Healthcare NHS Trust, London, UK
Corresponding Author:
Katherine M. Stenson, St George’s Vascular Institute, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK.
Email: kstenson@doctors.org.uk
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Original Article
Clinical and Applied
Thrombosis/Hemostasis
Volume 28: 1-10
© The Author(s) 2022
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/10760296221144307
journals.sagepub.com/home/cat
Introduction
Carotid endarterectomy (CEA) is the definitive treatment for
long-term stroke prevention in patients who have suffered a
recent cerebral ischemic event with moderate to severe internal
carotid artery stenosis.1,2 Patients with symptomatic carotid
stenosis of 50% to 99%, according to the North American
Symptomatic Carotid Endarterectomy Trial (NASCET) criteria,
or more than 70% according to the European Carotid Surgery
Trial criteria, should be assessed and referred urgently for
CEA.3–5 CEA is a procedure whereby the atherosclerotic
plaque is removed from the carotid artery via an arteriotomy.
Despite it demonstrating significant long-term benefits with
regard to primary and secondary stroke prevention and mortality
reduction, complications of the operation can provide significant
perioperative challenges.1,6
Perioperative bleeding is common in patients undergoingCEA
and othermajor vascular reconstructions. It iswell-recognized that
treatment before surgery with dual antiplatelet therapy reduces the
risk of perioperative stroke. The patient often also receive intraoperative
anticoagulation to further reduce thromboembolic risk,
however, these contribute to a significant risk of anastomotic
bleeding.7,8 These patients often have friable vessels with extensive
atherosclerotic disease and calcification, further contributing
to anastomotic bleeding risk.3,9
Anastomotic bleeding itself can be unpredictable, persistent,
and life-threatening. Postoperative hematoma after CEA has the
potential to cause rapid onset of airway obstruction, respiratory
failure, and emergency reintervention.10,11 In the NASCET
study postoperative neck hematomas occurred in 7.1% of
patients after CEA, which was subsequently identified as a statistically
significant risk factor for perioperative stroke and death
(14.9% in patients with wound hematoma, compared with 5.9%
in patients without hematoma).12 More recently, Baracchini
et al8 reported neck bleeding in 8.2% of 1458 cases undergoing
eversion CEA.
Hemostasis may be challenging in peripheral vascular surgery,
due to the requirement of direct arterial and arterial graft suturing.
The risk of anastomotic bleeding in vascular surgery may be
reduced bymeticulous technique, using fine needles, suture material,
and surgical loupes. The use of antiplatelet agents and systemic
anticoagulants in the prevention of thrombosis during
periods of operative vessel occlusion will increase the risk
despite good surgical technique. Increasingly, hemostatic agents
are being used as an adjunct to promote hemostasis.13
Rapid hemostasis during CEA results in shorter operative
times, decreased transfusion requirement, improved patient
recovery time, and decreased wound healing time.13 Adjuvant
hemostatic methods alongside accurate methods of primary
hemostasis may aid in achieving these outcomes.
Multiple hemostatic agents are available to the surgeon, with
the aim of controlling and reducing anastomotic bleeding but, to
date, a reliable option that is easy to use and shows good risk
and cost–benefit potential is not widely available. Those hemostatic
agents can be divided into 3 categories: hemostats, sealants,
and adhesives.13 Five classes of these agents have been
historically available: fibrin sealants, bovine collagen and
thrombin, cyanoacrylate, albumin cross-linked with glutaraldehyde,
and polyethylene glycol polymer.9 The self-assembling
peptide, RADA16, an absorbable hemostatic material, was
developed for use as a hemostat (PuraStat®, 3-D Matrix
Europe, Caluire and Cuire, France) for controlling intra- and
postoperative bleeding in diverse surgical procedures (eg,
bleeding from vascular anastomosis, small vessel hemorrhage
of the gastrointestinal tract and oozing from capillaries of the
parenchyma and surrounding tissues of solid organs). It is
made from a chain of 3 naturally occurring amino acids; arginine,
alanine, and aspartic acid bonded together and repeated
4 times to form a 16-amino acid oligo-peptide chain,
RADA16, as shown in Figure 1. It is a transparent, amphiphilic
self-assembling peptide (SAP), available in a prefilled syringe
as a 2.5% aqueous solution. Contact with the fluid of physiological
pH, such as blood causes the acidic peptide solution to be
neutralized and, as a result, the peptide molecule, which has a
β structure, quickly forms a peptide hydrogel. This hydrogel
coats and adheres to the point of vessel bleeding, forming a
mechanical barrier that effectively seals the damaged part of
the vessel. This facilitates coagulation deep into the gel, thus
aiding hemostasis. The gel remains in situ after surgery and is
gradually absorbed. The majority will have been absorbed
within 30 days, but some may remain in place for longer.14
RADA16 was commercialized under the name of PuraStat®
following Masuhara et al15 first demonstrating its safety and efficacy
as a hemostat in cardiac surgery. Since 2014, both pro-active
and reactive postmarket surveillance data have been collected to
monitor and record serious adverse events causally related to
PuraStat®, of which none have been declared as of July 2022.
Subsequent clinical trials have been carried out since 2014 to
assess and demonstrate the safety and efficacy of PuraStat® in
multiple surgical fields, including cardiology, hepatology, gastrointestinal,
otolaryngology, and endocrine surgery.16–24
Aim/Hypotheses
The objective of this postmarket clinical follow-up study is to
report safety and performance data from patients undergoing
elective CEA where the SAP, PuraStat®, was used for intraoperative
hemostasis.
The primary endpoint was defined as total time-tohemostasis
(TTH).
Secondary endpoints evaluated were blood loss, drainage
volume, ease of use of PuraStat®, and rate and quantity of
transfusion of blood products. Safety data were also collected
including reintervention for bleeding, adverse events, postoperative
complications, and length of hospital stay.
Methods
Study Design
This was a single-arm, prospective, multicenter study involving
consecutive patients undergoing CEA in whom RADA16, the
2 Clinical and Applied Thrombosis/Hemostasis
hemostatic agent was applied to the suture line after the removal
of arterial clamps. Ethics approval was obtained from all
centers. The study was registered at HRA under number 17/
LO/0082 and at ClinicalTrials.gov under the Identifier:
NCT03103282.
Patient Selection
Patients over the age of 18 years, undergoing elective CEA
either by direct closure (without the use of patch), patch reconstruction,
or eversion technique were screened for eligibility.
Those, undergoing elective CEA, requiring the use of
RADA16 were eligible for inclusion. Those with a known coagulation
disorder or hypersensitivity to any components of
RADA16 were excluded. No formal statistical hypothesis was
conducted to derive the sample size.
Patient Enrollment
Routine standard of care regarding the informed consent process
for CEA was followed independently of any information or discussion
relating to this study. Study inclusion was first discussed
at the preoperative visit. Informed consent forms related to the
study were provided to each site and were signed by the patients.
Once deemed eligible, patients were assigned a unique identification
number for the duration of the study.
Patient demographics, medical history, and their use of antiplatelet
or anticoagulant drugs were recorded prospectively,
alongside standard local site preoperative examinations and
blood tests (full blood count, pregnancy test, prothrombin
time, fibrinogen or partial thromboplastin time).
Procedure
CEA was undertaken by 7 senior surgeons with previous experience
with different hemostatic agents. CEA was carried out to
the standard of care of the local site by either patch reconstruction,
direct closure, or eversion technique, subject to the lead
surgeon’s discretion. CEA involves the removal of atherosclerotic
plaque via an arteriotomy in the internal carotid artery
(ICA). Direct closure involves closing the arteriotomy with
direct suturing of the ICA, whereas patch reconstruction
involves the incorporation of a synthetic, bovine pericardial,
or venous patch as the method of closure. The eversion technique
involves the disconnection of the ICA from the carotid
bulb via an arteriotomy. The ICA is then everted to allow for
the atherosclerotic plaque to be removed before the ICA is
re-anastomosed to the carotid bulb.25 All patients were on
dual antiplatelet therapy preoperatively and were administered
systemic intravenous heparin intraoperatively, as per local site
protocol.
Procedural instructions for PuraStat® use were provided to
the study sites. PuraStat® was supplied in prefilled syringes,
of either 1, 3, or 5 mL. Primary hemostasis was achieved
through techniques at the lead surgeon’s discretion, including
single pressure, and further monofilament sutures, with or
Figure 1. Constituents of PuraStat®. In contact with the fluid of physiological pH, the β sheet nanofiber network rapidly forms a hydrogel
creating a mechanical barrier to aid in hemostasis.14
Stenson et al 3
without pledgets, for bleeding in between existing sutures.
Cautery was not used on the suture line itself. RADA16 was
applied if oozing bleeding from suture lines was present after
the clamps on the vessel were removed. As much blood as possible
was removed from the bleeding site following initial
hemostasis before the application of RADA16. The syringe
nozzle was held as close to the tissue as possible to allow for
adequate application in a volume sufficient to fully cover the
bleeding site. The gel was left undisturbed until complete hemostasis
occurred. In some cases, more than one application or
syringe was required to achieve this and there was no
maximum number of applications defined.
The primary endpoint was defined as total time-tohemostasis
(TTH). TTH was measured using a stopwatch
from the initial application of RADA16 to the bleeding site,
after vessel clamp release, until all visible bleeding had
ceased, and complete hemostasis was judged as achieved by
the operator.
In the case of multiple applications of RADA16, TTH was
defined as the time from the very first application. TTH is a
well-accepted outcome measure for hemostasis and has been
used in previous postmarket studies evaluating the safety and
efficacy of PuraStat®.17,18 This should allow adequate comparability
of the results across the different surgical fields.
Secondary endpoints evaluated were blood loss, drainage
volume, ease of use of PuraStat®, and rate and quantity of
transfusion of blood products. Safety data were also collected
including reintervention for bleeding, adverse events, postoperative
complications, and length of hospital stay.
Surgeon-Assessed Outcomes
Surgeons were asked to categorize the degree of bleeding following
anastomosis as being “mild,” “moderate,” or “severe.”
They were asked to comment on the quality of the vessel
being treated as “poor,” “moderate,” or “good.” At the completion
of the procedure, investigators were asked to determine
hemostasis as “complete” or as “showing presence of bleeding.”
The ease of use of the PuraStat® application system was
assessed by the operating surgeons as “excellent,” “good,”
“fair,” or “poor.”
Follow-up Protocol
Patients were followed up at 24 h, at discharge, and at one
month postoperatively. One-month follow-up was completed
in person or over the phone. Primary endpoint data were collected
intraoperatively, whereas secondary endpoints and
safety data were collected throughout the study follow-up
period.
Statistical Analysis
Statistical analysis was undertaken using SAS System®, Version
9.4. No replacement of missing data has been performed.
Descriptive statistics were utilized with continuous variables
summarized as mean (with 95% confidence intervals [CIs]), standard
deviation, median, quartiles, and range. The number of
missing observations has also been summarized. Categorical variables
were summarized as percentages by categories.
All statistical analysis was performed on the intention-totreat
(ITT) population of the study, defined as all the patients
with signed informed consent forms that were treated with at
least one application of RADA16.
Results
Patient Recruitment and Enrollment
Eighty-nine patients were enrolled in the study between June
2017 and July 2019 (72 patients in 4 hospitals in the United
Kingdom and 17 patients in one hospital in Belgium).
Twenty-four (27%) of this cohort were excluded from the
ITT population as RADA16 was not used either because
patients were ineligible (9), or because there were no active
bleeding sites after primary hemostasis (9) for other reasons
not reported by the site (3), for unknown reasons (2), 1
patient who was eligible but did not have RADA16 applied
during the procedure. Recruitment and enrolment data are summarized
in Figure 2.
In the remaining 65 cases, RAD16 was used during elective
CEA, and these formed the ITT population. One patient completed
the study with a major deviation, whereby the site did
not use a stopwatch to measure the TTH resulting in a perprotocol
population (PP) of 64 participants. 24-h follow-up
and discharge data were complete for 100% of patients. 93.8%
(61) completed the 1-month follow-up visit, of which 83.6%
(51) were completed within the predefined study window.
Patient Demographics
Sixty-five patients underwent CEA with intraoperative use of
RADA16 and were included in the study. Of these, 51
(78.5%) of participants were male and 14 (21.5%) females,
with a mean age of 71.8±8.9 years (range 48-87 years).
Most of the participants, 60 (92.3%) had a normal physical
examination at the preoperative consultation, with a mean
body mass index of 26.3±5.3 kg/m2. 44 (68.8%) had a
history of smoking and 12 (18.5%) were diabetic. A total of
47 out of 63 (74.6%, data were missing for 2 patients), were
deemed at high risk, having an American Society of
Anesthesiologists (ASA) grade of 3 or more.26 Mean preoperative
systolic blood pressure was 135.7 ±19.9 mm Hg and diastolic
blood pressure was 71.5±13.8 mm Hg. Full patient
characteristics are presented in Table 1.
Procedure
Fifty-nine (90.8%) CEAs were performed using patch reconstruction,
of which most cases, 37 (56.9%), used a bovine pericardial
patch. The eversion technique was used in 4 (6.1%)
cases and direct closure (without a patch) was performed in 2
4 Clinical and Applied Thrombosis/Hemostasis
(3.1%) of cases. The mean duration of the procedure was 118±
35 min (range: 61-255 min). The mean carotid artery clamp
time was 35 min 12 s±19 min 59 s (range: 25 s-68 min),
with data reported in 59 cases.
After clamp removal, in 50 cases (76.9%) “rescue” sutures
were inserted to achieve primary hemostasis before the application
of RADA16. The quality of vessels at the suture or the
anastomotic site was reported as “good” in 51 cases (79.7%)
and “moderate” in 13 cases (20.3%). Data were missing for
one patient. No patients had suture site vessels deemed as
“poor” quality.
The mean total number of applications of PuraStat® was 1.3
±0.6, with the mean total amount of product used recorded as
1.7±1.1 mL.
Figure 2. Patient recruitment and enrolment flowchart.
Abbreviations: ITT, Intent To Treat; TTH, Time To Hemostasis; PP, Per Protocol.
Stenson et al 5
Bleeding and RADA16 Efficacy
The degree of bleeding prior to the application of RADA16 was
reported by the operating surgeon as “mild” in 59 cases (90.8%)
and “moderate” in 6 (9.2%), with no “severe” bleeding,
recorded. This classification was subjective and observerdependent.
RADA16 appeared to be effective in the majority
of cases.
In 59 cases (90.8%), investigators describe hemostasis as
“complete” including 3 cases where it had been obtained by
combining RADA16 with additional hemostatic action. In 6
cases (9.2%), the investigator reported ongoing “presence of
bleeding,” of these, 4 had decreased bleeding compared with
preapplication levels described by the investigator, and 2
showed no change in bleeding levels. Further action was
required to achieve hemostasis using additional rescue sutures
in 3 cases, compressions in 2, and the use of a fibrillar, surgical
absorbable hemostat in 1 case. Of the 59 cases that achieved
hemostasis the number of applications of the product was as
follows: 49 requiring 1 application, 7 requiring 2 applications,
and 3 required 3 applications of the product. Overall, 6 cases
(9.2%) did not achieve hemostasis using RADA16. Full data
on the bleeding condition after the RADA16 application are
shown in Table 2.
Primary Endpoint
The mean TTH reported was in seconds 83±105 (range:
4-653 s), with a median time of 52 s. TTH was predictably
greater in those with moderate bleeding compared with mild,
307 ±266 s and 66±63 s, respectively, and in those requiring
additional applications of RAD16. In 49 cases, 1 application
of RADA16 was used, with a mean TTH of 50±35 s. The
mean TTH in patients receiving 2 applications was 180±
79 s, and in those receiving 3 applications was 399±256 s.
Primary endpoint results for the ITT population are presented
in Table 3.
Secondary Endpoints
Secondary performance data included intraoperative blood loss,
drainage volume at 24 h postprocedure and at discharge, rate,
and quantity of transfusion of blood products received (intraoperatively
at 24 h postoperatively and overall), and ease of use
of PuraStat® during CEA.
Table 1. Demographics of the Patient Cohort Included in the
Statistical Analysis.
Characteristic
ITT
N=65
(n/N) %, (missing)
Smoking (44/64) 68.8%, (1)
Diabetes (12/65) 18.5%, (0)
Type I (1/12) 8.3%, (0)
Type II (11/12) 91.7%, (0)
Diabetes treatment (0)
Oral treatment (8/12) 66.7%, (0)
Insulin-dependent (4/12) 33.3%, (0)
Renal failure (2/65) 3.1%, (0)
Family History (of CVD) (19/65) 29.2%, (0)
ASA score (2)
1 (2/63) 3.2%
2 (14/63) 22.2%
3 (42/63) 66.7%
4 (5/63) 7.9%
5 (0) 0%
Other vascular condition (24/65) 36.9%, (0)
Other medical history (24/65) 36.9%, (0)
Abbreviations: ITT, Intent To Treat; CVD, Cardiovascular Disease; ASA score,
American Society of Anesthesiology score.
Table 3. Total Time-to-Hemostasis, Severity of Bleeding Pre-
Application, and Number of Applications (ITT Population).
Study primary endpoint
ITT population N=65 N Missing
N (%) or
mean ±SD
[95% CI] Range
Total TTH (sec) 59 0 83±105
[55-110]
4-653
Number of patients per
range of TTH
59 0
[ 4 (sec), 29 (Q25%)] 14 (23.7%)
[ 29 (Q25%), 53 (Q50%)] 16 (27.1%)
[ 53 (Q50%), 931
(Q75%)]
15 (25.4%)
[ 91 (Q75%), 653 (Max)] 14 (23.7%)
TTH per severity of bleeding
(sec)
Mild 55 0 66±63 5-401
Moderate 4 0 307±266 4-63
TTH per number of
applications of PuraStat®
(sec)
1 49 0 50±35 4-66
2 7 0 180 ±79 68-286
3 3 0 399±256 142-653
Abbreviations: TTH: Time To Hemostasis; sec: seconds.
Table 2. Condition After Application of PuraStat®.
Status postapplication (s)
ITT patients
n (%)
N=65
Missing 0
Complete hemostasis 59 (90.8%)
Persistent bleeding 6 (9.2%)
Severity of persistent bleeding
compared to before application
N=6
Identical 2 (33.3%)
Decreased 4 (66.7%)
Worse 0 (0.0%)
Abbreviation: ITT, Intent To Treat.
6 Clinical and Applied Thrombosis/Hemostasis
The mean intraoperative blood loss was 127 ±111.4 mL
(95% CI: 99.2-154.8; range: 0-600 mL), with data missing for
one case. The case recording 600 mL of blood loss required
no specific further action and no adverse event was reported.
At 24 h, 60 patients (92.3%) had a surgical drain in situ. Five
patients did not have a drain. The mean drainage volume was
49.0 ±51.2 mL (range: 0-230 mL) for 52 patients and drainage
volume data was missing in 13 patients. Two patients (3.1%)
received blood products intraoperatively, with a mean volume
of 580 ±113.1 mL received. Neither of these was related to
bleeding after the RADA16 application. No further blood products
were received throughout the study period.
Full data for secondary performance endpoints are presented
in Table 4.
Safety Outcomes
In 3 cases (4.6% [95% CI: 1.0%-12.9%] of the ITT population)
there was postoperative bleeding requiring a return to the theatre;
2 within 24 h and one within 15 days. These events were
resolved without sequelae and evaluated by the surgeons as
related to the vascular procedure, with no causal relationship to
RADA16. Adverse events (AEs) were described based on
System Organ Class (SOC) in the Medical Dictionary for
Regulatory Activities (MedDRA).27 After 1 month of follow-up,
24 AEs had been reported in 20 patients. Of these, there were 11
procedural complications, 6 nervous system disorders (including
3 strokes), 2 cardiac disorders, and one each of the following: ear
and labyrinthine, gastrointestinal, general disorders, infection,
and vascular disorders. Eleven AEs were reported at the time
of the procedure, 5 within 24-h postprocedure, 3 within 15
days, and 5 at up to 1 month postprocedure. Seventeen patients
(26.2%) had AEs related to their CEA, of these, 5 (7.7%) were
deemed serious adverse events (SAEs). The hematoma was specifically
reported in 6 cases (9.2%) at 24-h assessment, with one
of these requiring surgical revisions at 24 h. Two further hematomas
were recorded within 1 month of CEA but did not
require additional treatment.
Overall, 7 AEs in 7 different patients (10.8%) were deemed
SAEs by the investigators; of these, 3 were classed as stroke (1
hemorrhagic, 1 intraoperative, and 1 postoperative). The
remaining 4 SAEs were bradycardia, a hematoma, pneumonia,
and 1 death. The overall incidence of stroke was 4.6%. No
SAEs were considered to be related to RADA16.
Two AEs were considered device-related. Of these, one was
reported at 24-h postoperatively as a small hematoma that
required no further action to resolve. The second was reported
as a failure to achieve hemostasis after 3 applications of
RADA16, requiring the additional hemostatic effort of compression
of the carotid vessel with a surgical swab. Neither
were classed as serious, and no device or product deficiencies
were reported during the study.
Table 4. Secondary Performance Endpoints: Blood Loss During Surgery, Drain Insertion and Volume Drained, and Transfusion Products
Received.
Secondary endpoints
ITT population
N=65 N Missing
(n/N)% or
mean±SD [95% CI] Range
Blood loss assessed during the surgery (mL) 64 1 127±111.4 [99.2-154.8] 0.0-600.0
Drainage volume (mL) until drain removal
At 24-h postprocedure 52 13 49 ±51.2 [34.7-63.2] 0.0-230.0
At discharge 1 64 60
Rate of transfusion of blood products
At surgery 65 0
No 63 (96.9%)
Yes 2 (3.1%) [0.4%-10.7%]
At 24-h postoperation 65 0
No 65 (100%)
Yes 0 (0.00%)
At discharge 65 0
No 65 (100%)
Yes 0 (0.00%)
Overall 65 0
No 63 (96.9%)
Yes 2 (3.1%) [0.4%-10.7%]
Quantity of blood products and/or substitutes
At surgery 2 0 580 ±113.1 500-660
At 24-h postoperation 0 0
At discharge 0 0
Overall 2 0 580 ±113.1 500-660
Overall ease of use was deemed “good” or “excellent” in 93.8% of the patients (60.0% “excellent”). The ease of preparation, the application system, and the
application of the gel were graded as “excellent” or “good” in 100%. The most valuable properties of PuraStat®, as recorded by surgeons, were its transparency and
its overall ease of use.
Stenson et al 7
The mean length of hospital stay for the study group was 4.3
±11 days (range: 0-85 days). The overall mortality at 1-month
follow-up post-CEA was 1.5% [95% CI: 0.0%-8.3%].
Discussion
CEA is associated with an increased risk of bleeding intra- and
postoperatively.1,12 This risk can be mitigated using the meticulous
surgical techniques. In this study, once the anastomosis
was complete, primary hemostasis was undertaken using
methods at the lead surgeon’s discretion to ensure the integrity
of the suture line. Such methods would include simple pressure
or further monofilament sutures, with or without pledgets, for
bleeding in between existing sutures.
Techniques such as additional “rescue” sutures or electrocoagulation
may be utilized to achieve primary hemostasis.
Other methods that show hemostatic benefits include intraoperative
neck flexion as well as simple postoperative direct neck
pressure.11,28 Despite these options, the risk of bleeding is
still relatively high, reported as 8.2% by Baracchini et al8 for
eversion CEA. Increasingly, vascular surgeons are looking at
hemostatic agents to aid in reducing this risk.13 The mode of
action of PuraStat® is different from comparable products.
Self-assembling peptides in contact with the tissues rapidly
form a hydrogel, which acts as a barrier and blocks the flow
of blood from the wound.14 PuraStat® has been used successfully
as a hemostat in cardiovascular, gastrointestinal, otolaryngology,
and endocrine surgery.
This study has demonstrated RADA16 (PuraStat®) to be an
effective hemostatic agent in vascular surgery, successfully
controlling suture site and anastomotic bleeding in 90.8% of
cases. This has been achieved without prolonging the length
of the procedure, while gaining favorable assessment from the
surgeons in terms of the ease of use, with 93.8% of surgeons
assessing its overall ease of use as “good” or “excellent.”
Each of the surgeons operated on approximately the same
number of patients and therefore there is no bias in this evaluation,
which despite everything remains obviously subjective.
Mean TTH, reported in 59 patients, was recorded as 83±
1058 s and the primary hemostatic efficacy rate was 90.8%.
This predictably increased with the number of applications of
PuraStat® required and the amount of bleeding present prior
to application. Given the very small numbers that did not use
the patch technique in this study (6% eversion and 3% direct
closure), it would be difficult to glean any significant differences
in the incidence of bleeding when comparing the different
techniques. There is little in the literature to adequately compare
the incidence of bleeding complications when different techniques
are used. This is largely related to the fact that bleeding
is relatively uncommon and so the numbers available to
compare are too small to draw meaningful conclusions from.
Gisbert et al29 did not find any difference in bleeding when
comparing patch closure with eversion in a series of 455
patients.
The results are comparable to a study published in 2019 by
Morshuis et al,17 demonstrating the performance and safety of
PuraStat® in left ventricular assist device therapy support,
where complete hemostasis was achieved in 93.1% of surgical
sites with a mean TTH of 19.38 ±13.01 s. The results also
concur with the 2018 study by Giritharan et al16 that assessed
the safety and efficacy of PuraStat® in a range of cardiac surgical
procedures, reporting that PuraStat® was solely sufficient in
achieving complete hemostasis in 84% of cases. When compared
to other hemostatic agents available in cardiovascular
surgery, TTH achieved with PuraStat® appears favorable.
Nasso et al30 reported on a gelatin-thrombin-based hemostatic
agent in cardiac surgery with a mean TTH of 3.8±2.4 min
and successful hemostasis achieved in 91.8% of patients. Few
studies on the use of hemostatic agents in CEA exist. Pellenc
et al31 report preliminary results for a poly(glycerol-sebacate)
acrylate-based sealant for use in vascular reconstruction,
achieving complete hemostasis in 84% of cases. It is noteworthy
that the comparability of previously published data using
TTH as an outcome measure may be challenging since
varying definitions exist. Its calculation is also subjective to
the operator and study populations may differ significantly.
Stangenberg et al32 reported 1.7% of patients undergoing
CEA between 2012 and 2013 who received a transfusion of
blood products before discharge, while 2 patients in our study
were transfused during surgery and none before discharge
(3.1%). This should be taken in the context of the study populations,
with most patients receiving PuraStat® having an ASA
grade of 3 or more.
Adverse events were reported in 30.8% of cases in the
1-month follow-up period, of which only 2 (3.1%) were
related to the device and neither were serious. The rate of reoperation
for bleeding was reported as 4.6% (3 cases), comparable
with results published by Weinrich et al33 who reported a reoperation
rate of 3.5% after CEA in 565 patients. The mortality
rate during the study period was 1.5% (1 patient) and was unrelated
to the device. Kashyap et al34 reported a mortality rate of
0.7% after CEA in 371 patients.
Currently available hemostatic agents have the potential to
enable transmission of viral and prion diseases from human
blood component-based agents, and systemic inflammatory
response syndrome to animal-derived agents.35,36 The purely
synthetic nature of PuraStat® negates these risks. As summarized
by Sankar et al,14 the completely synthetic nature and
the transparent aspect of PuraStat® provide unique advantages.
The transparency of PuraStat®, reported as its best feature in
70.8% of cases, allows unique visualization of the bleeding
site after application, meaning potential revisions of primary
hemostasis can take place intraoperatively instead of requiring
subsequent re-exploration.14 The application method as a gel
in a syringe with a nozzle may also enhance precision in a congested
operating field. In addition, PuraStat® is ready to use in a
prefilled syringe that is stored at refrigerator temperature and is
thus immediately ready for use.
Vyas and Saha13 describe the ideal characteristics of a hemostatic
agent as being one that could combine biodegradability,
rapid action of hemostasis, and minimal side effects while preventing
thrombosis. Lumsden and Heyman9 described their
8 Clinical and Applied Thrombosis/Hemostasis
perceived ideal characteristics of a hemostat as “easily applied
in a controlled fashion, highly predictable in creating hemostasis,
and nontoxic and must not have an adverse effect on anastomotic
patency.” This study on CEA has been able to
demonstrate the safety and rapid efficacy of PuraStat®, alongside
its inherent ability to be naturally absorbed by the body and
the favorable opinion of surgeons in terms of its application and
ease of use.
Limitations of this study include patients not being stratified
according to operative technique and general risk factors, but
the study centers and the cohort of patients were homogenous.
The proportion of patients with an ASA grade greater than 3
was significantly high and could well have impacted on the
results reported. Any further analysis and comparison should
take this into account. A follow-up study with risk scores stratified
to evaluate their effects on PuraStat® efficacy and safety
may be useful.
TTH, although an accepted outcome measure for hemostasis,
can be defined in a variety of ways and is a possible
cofounder. The reporting of “complete hemostasis” is also subjective
to the observer operating the stopwatch, but evaluation
of complete hemostasis is common to all surgeons and TTH
has been widely used to assess the hemostasis efficacy, both
in the preclinical and clinical setting. However, the development
of a well-structured definition for TTH would be beneficial.
A systematic review of hemostasis in vascular surgery to
identify key outcomes and outcome measures on this topic,
along with subsequent development of a core outcome set
could help to provide unified direction in this area of research
and improve the comparability of studies.
Conclusion
This multicentre, postmarket clinical follow-up study was able
to confirm the safety and efficacy of 3-D Matrix’s PuraStat®
self-assembling peptide (RADA16) in the management of
bleeding during elective CEA and opens a promising new perspective
to manage suture bleeding in carotid endarterectomy.
PuraStat® provides a safe and effective option to aid hemostasis
in surgical situations where standard means of hemostasis are
insufficient or impractical. The efficacy is demonstrated
through the results achieved with a mean TTH of 83 s and a
complete hemostasis postapplication in 90.8% of cases. No
SAEs related to the device, or its application confirm its
safety, alongside low volumes of intraoperative blood loss
and the subsequent need for blood transfusion. However, the
efficacy of long-term hemostasis and reduction of relevant
hematoma need further evaluation in a larger cohort with a prospective
two-armed study design.
Acknowledgments
All of the authors would like to thank Dr Maurice Bagot d’Arc of
BluePharm for his invaluable help in preparing the manuscript for
publication.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Ethical Approval
The study was conducted in accordance with the ethical principles that
have their origins in the Declaration of Helsinki and the requirements
for medical device investigations as presented in EN/ISO 14155:2011,
Clinical investigation of medical devices for human subjects—Good
clinical practice; Annex X of the European Medical Devices
Directive 93/42/EEC, as amended by Directive 2007/47/EEC,
MEDDEV 2.7/4 and applicable local regulatory requirements. Ethics
approval was obtained from all centers. The registration number at
HRA 17/LO/0082 was granted in March 2017and the study was registered
under the ClinicalTrials.gov Identifier: NCT03103282.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
ORCID iD
Katherine M. Stenson https://orcid.org/0000-0002-1795-4578
References
1. Saha SP, Saha S, Vyas K. Carotid endarterectomy: current concepts
and practice patterns. Int J Angiology. 2015;24(3):223-235.
2. Jim J, Fairman R. Complications of carotid endarterectomy
[Internet]. UpToDate; 2020. [cited 2020 Dec 11]. Available
from: https://www.uptodate.com/contents/complications-of-carotidendarterectomy
3. North American Symptomatic Carotid Endarterectomy Trial
(NASCET) Steering Committee. North American symptomatic
carotid endarterectomy trial: Methods, patient characteristics,
and progress. Stroke. 1991;22(6):711-720.
4. European Carotid Surgery Trialists’ Collaborative Group.
Randomised trial of endarterectomy for recently symptomatic
carotid stenosis: final results of the MRC European carotid
surgery trial (ECST). Lancet. 1998;351(9113):1379-1387.
5. National Institute for Health and Care Excellence. Stroke and transient
ischaemic attack in over 16s: diagnosis and initial management
[Internet]. NICE; 2019, 2019 May 1. (NICE guideline
[NG128]).
6. Barnett H, Taylor D, Eliasziw M, et al. Benefit of carotid endarterectomy
in patients with symptomatic moderate or severe stenosis.
N Engl J Med. 1998;339(20):1415-1425.
7. Jones DW, Goodney PP, Conrad MF, et al. Dual antiplatelet
therapy reduces stroke but increases bleeding at the time of
carotid endarterectomy. J Vasc Surg. 2016;63(5):1262-1270.e3.
8. Baracchini C, Gruppo M, Mazzalai F, Lorenzetti R, Meneghetti G,
Ballotta E. Predictors of neck bleeding after eversion carotid endarterectomy.
J Vasc Surg. 2011;54(3):699-705.
9. Lumsden A, Heyman E. Prospective randomized study evaluating
an absorbable cyanoacrylate for use in vascular reconstructions. J
Vasc Surg. 2006;44(5):1002-1009.
Stenson et al 9
10. McCready R, Siderys H, Pittman J, et al. Delayed postoperative
bleeding from polytetrafluoroethylene carotid artery patches. J
Vasc Surg. 1992;15(4):661-663.
11. Tamaki T, Morita A. Neck haematoma after carotid endarterectomy:
risks, rescue, and prevention. Br J Neurosurg. 2019;
33(2):156-160.
12. Ferguson G, Eliasziw M, Barr H, et al. The North American symptomatic
carotid endarterectomy trial: surgical results in 1415
patients. Stroke. 1999;30(9):1751-1758.
13. Vyas KS, Saha SP. Comparison of hemostatic agents used in vascular
surgery. Expert Opin Biol Ther. 2013;13(12):1663-1672.
14. Sankar S, O’Neill K, Bagot D’Arc M, et al. Clinical use of the selfassembling
peptide RADA16: a review of current and future
trends in biomedicine. Front Bioeng Biotechnol. 2021;2(9):
679525. doi:10.3389/fbioe.2021.679525.
15. Masuhara H, Fujii T, Watanabe Y, Koyama N, Tokuhiro K. Novel
infectious agent-free hemostatic material (TDM-621) in cardiovascular
surgery. Ann Thorac Cardiovasc Surg. 2012;18(5):444-451.
16. Giritharan S, Salhiyyah K, Tsang G, Ohri S. Feasibility of a novel,
synthetic, self-assembling peptide for suture-line haemostasis in
cardiac surgery. J Cardiothorac Surg. 2018;13(1):68.
17. Morshuis M, Schönbrodt M, Gummert J. Safety and performance
of a self-assembling peptide haemostat for the management of
bleeding after left ventricular assist device implantation: outcomes
of a post market clinical follow-up study. J Heart Lung
Transplant. 2019;38(4):S194.
18. Nahm C, Popescu I, Botea F, et al. A multi-center post-market
clinical study to confirm safety and performance of PuraStat® in
the management of bleeding during open liver resection. HPB
(Oxford). 2021;24(5):700-707. doi:10.1016/j.hpb.2021.09.020.
19. Subramaniam S, Kandiah K, Chedgy F, et al. A novel selfassembling
peptide for hemostasis during endoscopic submucosal
dissection: a randomized controlled trial. Endoscopy 2020;53(1):
27-35. doi:10.1055/a-1198-0558.
20. Uraoka T, Ochiai Y, Fujimoto A, et al. A novel fully synthetic and
self-assembled peptide solution for endoscopic submucosal
dissection-induced ulcer in the stomach. Gastrointest Endosc.
2016;83(6):1259-1264.
21. de Nucci G, Reati R, Arena I, et al. Efficacy of a novel selfassembling
peptide hemostatic gel as rescue therapy for refractory
acute gastrointestinal bleeding. Endoscopy. 2020;52(9):773-779.
22. Lee MF, Ma Z, Ananda A. A novel haemostatic agent based on
self-assembling peptides in the setting of nasal endoscopic
surgery, a case series. Int J Surg Case Rep. 2017;41:461-464.
23. Friedland Y, Ha J, Bagot d’Arc M, Delin C. ‘The use of selfassembling
peptides (PuraStat™) in functional endoscopic sinus
surgery for haemostasis and reducing adhesion formation. A
case series of 94 patients. Surg Technol Int. 2022;41:sti41/1594.
24. Gangner Y, Bagot d’Arc M, Delin C. The use of self-assembling
peptides (PuraStat) for hemostasis in cervical endocrine surgery. A
real-life case series of 353 patients. Int J Surg Case Rep.
2022;94:107072. doi:10.1016/j.ijscr.2022.107072.
25. Galyfos G, Geropapas G, Kerasidis S, Kastrisios G. Carotid endarterectomy:
which technique prevails? J Vasc Endovascular
Surg. 2016;1(1):5.
26. American Society of Anesthesiologists. ASA Physical Status
Classification System. [Internet]. 2020 [cited 2020 Dec 15].
Available from: https://www.asahq.org/standards-and-guidelines/
asa-physical-status-classification-system
27. MedDRA. MedDRA Introductory Guide Version 14.0. [Internet].
2011 [cited 2020 Dec 15] Available from: https://www.who.int/
medical_devices/innovation/MedDRAintroguide_version14_0_
March2011.pdf
28. Saghir R, Humm G, Rix T. Haematomas after carotid endarterectomy
can be reduced by direct pressure to the neck postoperatively.
Ann R Coll Surg Engl. 2018;100(7):580-583.
29. Gisbert SM, Sala Almonacil V, Zaragozá García JM, Genovés
Gascó B, Gómez Palonés FJ, Ortiz Monzón M. Predictors of cervical
bleeding after carotid endarterectomy. Ann Vasc Surg.
2014;28(2):366-374. doi:10.1016/j.avsg.2013.04.011. Epub 2013
Sep 29.
30. Nasso G, Piancone F, Bonifazi R, et al. Randomized clinical trial
of the FloSeal matrix sealant in cardiac surgery. Ann Thorac Surg.
2009;88(5):1520-1526.
31. Pellenc Q, Touma J, Coscas R, et al. Preclinical and clinical evaluation
of a novel synthetic bioresorbable, on-demand, lightactivated
sealant in vascular reconstruction. J Cardiovasc Surg.
2019;60(5):599-611.
32. Stangenberg L, Curran T, Shuja F, Rosenberg R, Mahmood F,
Schermerhorn ML. Development of a risk prediction model for
transfusion in carotid endarterectomy and demonstration of costsaving
potential by avoidance of “type and screen”. J Vasc
Surg. 2016;64(6):1711-1718.
33. Weinrich M, Schindler P, Kundt G, Klar E, Bünger CM. Influence
of local hemostatic and antiplatelet agents on the incidence of
bleeding complications in carotid endarterectomies. Clin
Hemorheol Microcirc. 2014;58(1):71-79.
34. Kashyap V, King AH, Foteh MI, et al. A multi-institutional analysis
of transcarotid artery revascularization compared to carotid
endarterectomy. J Vasc Surg. 2019;70(1):123-129.
35. Despotis G, Avidan M, Eby C. Prediction and management of bleeding
in cardiac surgery. J Thromb Haemostasis. 2009;7(s1):111-117.
36. Taflampas P, Sanidas E, Christodoulakis M, Askoxylakis J,
Melissas J, Tsiftsis DD. Sealants after axillary lymph node dissection
for breast cancer: good intentions but bad results. Am J Surg.
2009;198(1):55-58.
10 Clinical and Applied Thrombosis/HemostasisREC name
London - Surrey Borders Research Ethics Committee
REC reference
17/LO/0082
Date of REC Opinion
14 Mar 2017
REC opinion
Further Information Favourable Opinion