(274 days)
Not Found
Not Found
No
The device description and intended use clearly define it as a chemical solution for flushing and storing vascular grafts. There is no mention of any software, algorithms, or data processing that would indicate the use of AI/ML. The performance studies focus on clinical outcomes related to the solution's effect on graft patency and patient safety, not on the performance of any AI/ML component.
Yes
The device is intended for flushing and storage of saphenous vein grafts during Coronary Artery Bypass Grafting Surgeries, which is a medical intervention to maintain the viability of tissue for transplant, directly contributing to the therapeutic outcome of the surgery.
No
Explanation: The device is a solution used for flushing and storage of saphenous vein grafts during Coronary Artery Bypass Grafting Surgeries. It is a therapeutic/preservation solution, not a device used to diagnose a medical condition.
No
The device description clearly states it is a "solution" supplied in containers, indicating a physical substance, not software.
Based on the provided information, this device is not an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use is for flushing and storage of vascular conduits (saphenous vein grafts) during surgery. This is a direct application to a biological material outside of the body, but it's for the purpose of preserving the material for later implantation, not for diagnostic testing of a sample from the body.
- Device Description: The device is a solution used to maintain the viability of the graft. It's a preservation medium, not a reagent or instrument used to analyze a biological sample for diagnostic purposes.
- Lack of Diagnostic Activity: There is no mention of the device being used to test a sample from a patient to diagnose a condition, monitor a treatment, or screen for a disease. The performance studies focus on the outcomes of the surgical procedure and the condition of the graft after implantation, not on diagnostic measurements.
- No Mention of IVD-Specific Terms: The description and studies do not use terminology typically associated with IVDs, such as "analyte," "assay," "calibration," "quality control," or "diagnostic accuracy."
In summary, the DuraGraft Vascular Conduit Solution is a surgical aid used to preserve biological material for transplantation, not a device used for in vitro diagnostic testing of a patient sample.
N/A
Intended Use / Indications for Use
DuraGraft Vascular Conduit Solution is a solution indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts from harvesting through grafting for up to 4 hours.
Product codes (comma separated list FDA assigned to the subject device)
QEJ
Device Description
DuraGraft Vascular Conduit Solution is a clear, colorless to slightly yellow, aseptically processed, non-pyrogenic solution for room temperature flushing and storage of vascular conduits used during the harvesting and grafting interval in Coronary Artery Bypass Grafting (CABG) surgeries.
DuraGraft Vascular Conduit Solution is supplied in two separate containers composed of a Solution A (237.5mL) and a Solution B (12.5-13.5mL). Solution A is mixed with 12.5mL of Solution B prior to use.
DURAGRAFT Vascular Conduit Solution has an osmolality of about 305 mOsmol/kg, viscosity of 1.06 cST, a sodium concentration of 155-160 mEq/L, a potassium concentration of 5.8 mEq/L, and a pH of about 7.4 at room temperature. Composition and molar concentrations of DuraGraft (mixed solution) is given in Table 1 below.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
saphenous vein grafts
Indicated Patient Age Range
adult patients, >18 years and
N/A
0
DE NOVO CLASSIFICATION REQUEST FOR DURAGRAFT VASCULAR CONDUIT SOLUTION
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Flushing and storage solution for vascular autografts at room temperature. A flushing and storage solution for vascular autografts at room temperature is a device that is used for flushing or short-term storage of vascular grafts. This generic type of device is intended to maintain cell viability and structural integrity of vascular grafts during shortterm storage at room temperature during the surgical procedure.
NEW REGULATION NUMBER: 21 CFR 876.4100
CLASSIFICATION: Class II
PRODUCT CODE: QEJ
BACKGROUND
DEVICE NAME: DuraGraft Vascular Conduit Solution
SUBMISSION NUMBER: DEN230002
DATE DE NOVO RECEIVED: January 3, 2023
SPONSOR INFORMATION:
Marizyme, Inc. 555 Heritage Drive Suite 205 Jupiter, FL 33458-5290
INDICATIONS FOR USE
The DuraGraft is indicated as follows:
DuraGraft Vascular Conduit Solution is a solution indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts from harvesting through grafting for up to 4 hours.
LIMITATIONS
The sale, distribution, and use of the DuraGraft Vascular Conduit Solution are restricted to prescription use in accordance with 21 CFR 801.109.
1
DuraGraft Vascular Conduit Solution is not intended for direct injection or intravenous infusion.
DuraGraft Vascular Conduit Solution includes a component, L-arginine. L-arginine may cause an allergic reaction in certain patients.
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
DuraGraft Vascular Conduit Solution is a clear, colorless to slightly yellow, aseptically processed, non-pyrogenic solution for room temperature flushing and storage of vascular conduits used during the harvesting and grafting interval in Coronary Artery Bypass Grafting (CABG) surgeries.
DuraGraft Vascular Conduit Solution is supplied in two separate containers composed of a Solution A (237.5mL) and a Solution B (12.5-13.5mL). Solution A is mixed with 12.5mL of Solution B prior to use.
DURAGRAFT Vascular Conduit Solution has an osmolality of about 305 mOsmol/kg, viscosity of 1.06 cST, a sodium concentration of 155-160 mEq/L, a potassium concentration of 5.8 mEq/L, and a pH of about 7.4 at room temperature. Composition and molar concentrations of DuraGraft (mixed solution) is given in Table 1 below.
| SOLUTIONS A + B (19:1 ratio) | |
|---|---|
| Ingredients | Concentration in mM |
| Calcium chloride | 0.95 |
| Potassium chloride | 5.37 |
| Potassium phosphate monobasic | 0.44 |
| Magnesium sulfate | 0.41 |
| Magnesium chloride | 0.49 |
| Sodium chloride | 136.89 |
| Sodium bicarbonate | 4.29 |
| Sodium phosphate dibasic | 0.19 |
| L-Glutathione | 1.01 |
| D-Glucose | 5.55 |
| L-Arginine | 0.86 |
| L-Ascorbic acid | 0.51 |
| pH | 7.4 |
| Water For Injection |
Table 1: Composition of DuraGraft (Mixed Solution)
2
Please refer to the labeling for additional device description details.
SUMMARY OF NONCLINICAL/BENCH STUDIES
BIOCOMPATIBILITY/MATERIALS
DuraGraft is considered to have limited indirect contact with the blood (, osmolality per USP , and particle count per USP . Testing was also conducted to evaluate the stability of Solution B (arginine, glucose, ascorbic acid, and glutathione) at time points from 0 to 36 months to support the device stability and 3-year shelf-life.
3
The following preclinical studies support DuraGraft for use as a short-term flushing and storage solution for vascular conduits.
| Publication | Experimental Conditions | Summary and Conclusions |
|---|---|---|
| Pachuk et al., | ||
| 20191 | Human saphenous vein (HSV) | |
| segments collected from 9 patients | ||
| undergoing CABG surgery stored for | ||
| up to 5 hours in DuraGraft or normal | ||
| saline solution (NSS) | ||
| Pig mammary vein segments were | ||
| flushed and stored with DuraGraft or | ||
| NSS for 45 minutes and 24 hours. | Graft cell viability was maintained in human saphenous vein | |
| segments when the segments were flushed and stored in DuraGraft | ||
| up to 5 hours. | ||
| Loss of graft cell viability was observed within 15 minutes | ||
| following flushing and storage in NSS. | ||
| H&E staining and Immunohistochemistry staining for CD31 and | ||
| von Willibrand factor (vWF) showed normal morphology by H&E | ||
| staining and strong immunostaining of endothelial surface markers | ||
| CD31 and vWF that was continuous across the endothelium at both | ||
| timepoints for veins stored in DuraGraft. | ||
| NSS stored veins had normal morphology by H&E staining at 45 | ||
| minutes but displayed multifocal aggregation of and missing | ||
| patches of endothelium at 24 hours. CD31 and vWF staining was | ||
| weaker for NSS stored grafts. | ||
| Korkmaz-Icoz | ||
| et al., 20212 | Rat thoracic aortic rings undergoing | |
| cold ischemic storage in either | ||
| DuraGraft or NSS at 4 °C for 24 hours | ||
| were incubated in an organ bath | ||
| culture containing 200µM sodium | ||
| hypochlorite for 30 minutes to induce | ||
| free radical formation as seen in | ||
| reperfusion. | Vasoactive physiologic arterial dysfunction was observed when | |
| aortic rings were stored in saline. | ||
| Aschacher et | ||
| al., 20213 | Radial Artery and HSV segments from | |
| 23 patients undergoing CABG surgery | ||
| were flushed and stored in either | ||
| DuraGraft or Ringers lactate solution | ||
| (RL) at room temperature for 60 | ||
| minutes or times up to 3 hours at room | ||
| temperature. | DuraGraft treated grafts showed normal endothelial and sub- | |
| endothelial structure whereas RL-treated grafts showed damaged | ||
| endothelial surface and beginning incongruence of intimal | ||
| structure. | ||
| DuraGraft treated grafts were associated with a lower level of | ||
| reactive oxygen species that correlated with a reduction of hypoxic | ||
| damage and significant increase in oxidation-reduction potential. |
Table 2. Preclinical Studies Supporting DuraGraft
SUMMARY OF CLINICAL INFORMATION
DuraGraft Prospective Randomized Study
The sponsor conducted a prospective, multicenter, randomized controlled trial outside of the U.S. to evaluate the effects of DuraGraft on graft level anatomic parameters (Perrault 2019)4. The study employed a "within-patient control" design, in which patients received both a control saline-treated saphenous vein graft (SVG) and a DuraGraft-treated SVG, randomly assigned per graft. The initial trial included multidetector computed tomography (MDCT) evaluation at 1 and 3 months. Follow-up was extended to 1-year with an additional MDCT evaluation in the second protocol requiring re-consenting the patients. Safety was assessed in both protocols through the incidences of vein graft thrombosis/occlusion, composite safety events, adverse events and SAEs. The primary safety endpoint for both protocols was the incidence of graft thrombosis/occlusion. Secondary safety endpoints included a composite safety endpoint consisting of Major Adverse Cardiac Events (MACE) (deaths, myocardial infarction (MI) and repeat revascularization), increased angina, arrhythmia, shortness of breath, decreased lumen change, graft occlusion, significant stenosis based on Fitzgibbon's scale B and O, if determined to be related to a specific graft, and incidence of adverse events (AE) and serious adverse events (SAE).
4
A total of 125 patients were randomized and enrolled from September 2014 to December 2016 at seven investigational sites in Canada, Ireland, and Denmark. 125 grafts were treated with DuraGraft, and 125 grafts treated with saline. Mean Society of Thoracic Surgeons score for mortality was 0.9 ± 0.6 and mean European System for Cardiac Operative Risk Evaluation II score was 1.1 ± 0.6. Grafts were assessed using serial MDCT at 1 month (n=116), 3 months (n=118), and 12 months (n=97), respectively.
Inclusion & Exclusion Criteria:
Inclusion Criteria:
-
- Subject to undergo primary, multi-vessel CABG with at least two SVGs
-
- Subject >18 years and 2.5x upper limit of normal (ULN) or conjugated bilirubin >1.5x ULN
-
- Subject had any condition or disease detected prior to study start that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the investigator (e.g., drug dependence, mental illness)
5
-
- Subject had uncontrolled diabetes mellitus (HbA1C >10%)
-
- Subject had any confirmed significant allergic reactions against any drug or multiple allergies (non-active hav fever is accepted)
-
- Subject who required uninterrupted use of systemic steroids or immunosuppressive agents
-
- Subject had platelet count 62% (Hb >18 g/dL) or 160 mmHg)
-
- Subject with prior severe reaction to contrast dye
Results:
The results of the safety endpoint analysis is exhibited below (Table 3). Vein graft occlusions were observed in 7.2% of the DuraGraft treated grafts and 8.8% of the saline treated grafts. According to the Fitzgibbon classification, a stenosis type B (flow limited) or type O (occlusion) was observed in 1.6% of the grafts in the DuraGraft group and 2.4% of the saline group. No MACE events were observed in the DuraGraft group compared to 1 in the saline group and in particular no deaths were observed in either group. The composite event rate was 8.8% for DuraGraft treated grafts and 11.2% for saline treated grafts.
Table 3. Adjudicated safety outcomes after graft treatment by either DuraGraft or saline after a follow-up duration of 110.3 patient-years (1 year follow-up timepoint)
| Outcome | DuraGraft
(n = 125) | Saline
(n = 125) |
|-------------------------------------|------------------------|---------------------|
| Major adverse
cardiac events† | 0 | 1 (0.8) [0.009] |
| Composite end point | 11 (8.8) [0.100] | 14 (11.2) [0.127] |
| Death | 0 | 0 |
| Myocardial infarction | 0 | 1 (0.8) [0.009] |
| Repeat revascularization | 0 | 0 |
| Increased angina | 0 | 1 (0.8) [0.009] |
| Increased arrhythmia | 0 | 0 |
| Increased shortness
of breath | 0 | 0 |
| Vein graft thrombosis/
occlusion | 9 (7.2) [0.082] | 11 (8.8) [0.100] |
| Fitzgibbon
class B and O | 2 (1.6) [0.018] | 3 (2.4) [0.027] |
Values are n (%) [number of events per patient-year]
- Death, myocardial infarction, or repeat revascularization.
1Composite of all adverse events
*Perrault et al., JTCVS 2019
6
MDCT analysis revealed that there was no significant difference between the DuraGraft group and the saline group in terms of change in mean wall thickness between 1 and 3 months in the analysis of whole grafts. However, at 12 months, DuraGraft treated SVGs had smaller mean wall thickness versus their saline-treated counterparts 0.12±0.06 mm vs 0.20±0.31 mm (Figure 1) and the change in maximal focal narrowing 0.2 ± 3.8 mm versus 4.7 ± 12.7 mm (Figure 2).
Image /page/6/Figure/1 description: This image is a graph titled "Wall Thickness Whole Graft" that compares the wall thickness of DuraGraft and Saline over a period of 12 months. The x-axis represents the months, ranging from 1 to 12, while the y-axis represents the wall thickness in millimeters, ranging from 0 to 0.25. The graph shows that the wall thickness of Saline is initially lower than DuraGraft, but it increases rapidly and then decreases slowly, while the wall thickness of DuraGraft remains relatively constant over the 12 months.
Figure 1: Wall thickness analysis by MDCT for whole graft
Image /page/6/Figure/3 description: The image is a title for a figure. The title reads, "Figure 2: Maximum Focal Narrowing analysis by MDCT for whole graft". The title is written in a clear, legible font. The title is centered and easy to read.
Image /page/6/Figure/4 description: This image is a graph titled "Maximal Focal Narrowing Whole Graft". The graph compares DuraGraft and Saline over a period of months. The x-axis represents the months, ranging from 1 to 12, and the y-axis represents the value in mm, ranging from 0 to 0.2. The graph shows that Saline has a higher value than DuraGraft.
DuraGraft EU Registry
The DuraGraft EU Registry5 is an ongoing European post-market study designed to support an international CABG registry database used to assess patients receiving DuraGraft during CABG surgery and whose free vascular grafts (4,454 venous grafts and 586 arterial conduits) have been treated with DuraGraft. A total of 2,964 patients were enrolled in the Registry, which enrolled patients between December 2016 and August 2019. There were 45 enrolling centers in eight countries: Austria, Germany, Ireland, Italy, Spain, Switzerland, Turkey and United Kingdom. Follow-up data has been completed out to one (1) year and will continue for up to five (5) years.
The subjects have an average age of 67.8 ±9.2 years (range 33 - 90 years). The majority of subjects were males (82.3%, 2438/2964) and were Caucasian (88.3%, n=2610/2956). The majority of subjects had a history of hypertension 84.4% (2486/2946), dyslipidemia 76.9% (2251/2929), and diabetes was present in 43.7% (1294/2962). The overall mean EuroSCORE II (ESII) for all patients is 2.6 ± 3.7 (n=2964). For CABG only patients (n=2532), the mean score is 2.3 ± 3.4 and for CABG +valve patients (n=432) is 4.3 ± 5.0.
Results:
7
In the total study population, 120 (4.1%) patients experienced a MACE at 30 days and 7.4% at 1 year. The 30-day incidence of death, myocardial infarction and repeat revascularization was 2.7%, 1.6% and 1.1%, respectively for all patients, isolated CABG and CABG + valve cohorts and at 1 year was 5.2%, 2.2% and 2.1%, respectively. In the total population, 2.3% of the patients experienced a stroke at 1 year. The 1-year all-cause death rate was 5.2% (148/2964). 30day and 1-year Kaplan Meir rates for MACE are given in Table 4.
In the isolated CABG group, the 30-day MACE rate was 3.5% with all-cause death (2.3%), myocardial infarction (1.3%), and repeat revascularization (1.0%). The I-year MACE rate was 6.6% with all-cause death (4.4%), myocardial infarction (2.0%), and repeat revascularization (2.2%).
The 30-day MACE rate for the combined CABG + valve groups was 7.5% with rates of death 5.4%, myocardial infarction 3.1% and repeat revascularization 0.7%. The 1-year MACE rate was 12.0% with rates of death 9.9%, myocardial infarction 3.3% and repeat revascularization 1.3% Cumulative incidence of primary endpoints and incidents are shown in Figure 3.
| | All patients
(n=2964)
% (No. of events) | | | Isolated CABG
(n=2532)
% (No. of events) | | CABG and valve
(n=432)
% (No. of events) | |
|---------------------------------|-----------------------------------------------|------------|--|------------------------------------------------|------------|------------------------------------------------|------------|
| | 30 days | 1 year | | 30 days | 1 year | 30 days | 1 year |
| MACE | 4.1% (120) | 7.4% (210) | | 3.5% (88) | 6.6% (160) | 7.5% (32) | 12.0% (50) |
| MACCE | 5.2% (153) | 8.6% (247) | | 4.6% (115) | 7.8% (190) | 8.9% (38) | 13.6% (57) |
| All-Cause Death | 2.7% (80) | 5.2% (148) | | 2.3% (57) | 4.4% (107) | 5.4% (23) | 9.9% (41) |
| Cardiovascular Death | 2.7% (80) | 4.5% (130) | | 2.3% (57) | 3.8% (92) | 5.4% (23) | 9.1% (38) |
| Myocardial Infarction | 1.6% (46) | 2.2% (63) | | 1.3% (33) | 2.0% (49) | 3.1% (13) | 3.3% (14) |
| All Repeat
Revascularization | 1.1% (31) | 2.1% (58) | | 1.1% (28) | 2.2% (53) | 0.7% (3) | 1.3% (5) |
| PCI | 0.8% (22) | 1.8% (48) | | 0.8% (21) | 1.9% (45) | 0.2% (1) | 0.8% (3) |
| Re-CABG | 0.3% (9) | 0.3% (10) | | 0.3% (7) | 0.3% (8) | 0.5% (2) | 0.5% (2) |
| Stroke | 1.7% (50) | 2.3% (65) | | 1.5% (37) | 1.9% (46) | 3.1% (13) | 4.6% (19) |
Table 4. 30-Day and 1-Year Kaplan Meier rates for MACE
- Percentages indicate cumulative event rates by Kaplan Meier estimates.
** MACE: major adverse cardiac events: MACCE: major adverse cardine and cerebrovascular events, PCI percutaneous coronary intervention, CABG, coronary artery bypass graffing,
8
Image /page/8/Figure/0 description: The image contains four cumulative incidence plots comparing different surgical procedures. The plots show the cumulative incidence of MACCE (major adverse cardiac and cerebrovascular events), mortality, myocardial infarction (MI), and revascularization over a 12-month period. Each plot compares "Isolated CABG", "CABG + Valve", and "All Subjects", with the number of patients at risk at different time points listed below each plot. The cumulative incidence at 12 months varies across the different outcomes and surgical groups.
IBJ All Dealt
Figure 3: Cumulative incidence of Primary endpoints and components (A.) MACE
Figure 3: Cumulative incidence of (A) the primary outcome; Major Adverse Cardiac Events (MACE); and the individual components of the primary outcome (B) all-cause death; (C) myocardial infarction; (D) repeat revascularization, at 1 year.
Propensity Matched Comparison of DuraGraft EU Registry to STS Registry
To compare mortality of patients in the single arm DuraGraft Registry, the Society of Thoracic Surgery (STS) Database was identified and determined suitable for use as a contemporaneous control. 2532 patients underwent isolated CABG surgery in the DuraGraft Registry between December 2016 and August 2019. 294.725 isolated CABG patients were identified in the STS Registry who were operated on between 2016 and had at least 1 year mortality data available from linkage to the US National Death Index (NDI), a database maintained by the National Center for Health Statistics (NCHS), which captures all death records for the US and US territories. An analysis was conducted comparing Isolated CABG patients from the DuraGraft Registry to a propensity matched control group from the STS Registry Adult Cardiac Surgery Database. 2400/2532 patients were matched from the DuraGraft cohort to 2400 patients in the STS Database, matching on the following 35 prespecified variables, selected to be predictive of mortality risk in the operative, peri-operative, and follow-up periods.
Demographics
-
- Age
-
- Male sex
-
- Black race
9
Cardiac Risk Factors
-
- BMI 2.0 mg/dl)
-
- Renal dialysis
-
- Peripheral vascular disease
-
- Pulmonary hypertension
-
- History of pulmonary disease
-
- History of CVA
Pre-Operative Cardiac Status
-
- MI 24h
-
- Unstable angina
-
- Congestive heart failure
-
- Cardiogenic shock
-
- Pre-operative atrial fibrillation
-
- Re-operation
-
- Left ventricular function (EF 50%
-
- Three (3) vessel disease
-
- Previous CABG
-
- Previous PCI
Surgical Technique
-
- Number of distal anastomoses
-
- On pump status
-
- Presence of LIMA graft
-
- Number of arterial grafts
-
- Number of venous grafts
-
- All arterial grafts
-
- All venous grafts
-
- Harvesting technique endoscopic
Results:
The cumulative incidence of mortality through 36 months of follow up in the 2,400 propensity matched DuraGraft and STS registry subjects is presented as Kaplan Meier estimates in Figure 4 And Table 5. At 30 days and 12 months the mortality estimate in DuraGraft was 2.38% [95% CI, 1.84% - 3.07%] and 4.32% [CI, 3.58% - 5.22%] compared to the STS Registry patients 1.96% [95% CI 1.47% - 2.60%] and 4.79% [95% CI 4.01% - 5.72%], respectively. At 36 months the
10
mortality estimate in DuraGraft patients was reduced compared to the STS Registry patients (7.37% [95% C1, 6.36% - 8.53%] vs. 9.65% [95% C1 8.37% - 11.10%]).
Figure 4. Kaplan Meier estimates of all-cause mortality through 36 months in 2400 DuraGraft patients and Kaplan Meier estimates of all-cause mortality through 36 months in 2400 Propensity Matched STS patients
Image /page/10/Figure/2 description: The image is a graph comparing the cumulative mortality rate between DuraGraft and a control group (STS). The x-axis represents time, ranging from 0 to 36, while the y-axis represents the cumulative mortality rate, ranging from 0% to 12%. The DuraGraft group, represented by a solid black line, shows a lower cumulative mortality rate compared to the control group, which is represented by a dashed red line. At the end of the observed period, the DuraGraft group has a mortality rate of approximately 7%, while the control group has a mortality rate of approximately 9.5%.
Time (Months)
Table 5. Kaplan Meier estimates of all-cause mortality through 36 months in 2400 DuraGraft patients that were Propensity Matched to STS patients. Product Limit (PL) Estimates.
| Time
Points
| (days) | DuraGraft | STS Registry | ||||||
|---|---|---|---|---|---|---|---|---|
| Number | ||||||||
| at Risk | Number | |||||||
| Failed | Survival | |||||||
| Estimate | Standard | |||||||
| Error | Number | |||||||
| at Risk | Number | |||||||
| Failed | Survival | |||||||
| Estimate | Standard | |||||||
| Error | ||||||||
| 0 | 2400 | 1 | 99.96% | 0.04% | 2400 | 1 | 99.96% | 0.04% |
| 30 | 2341 | 57 | 97.62% | 0.31% | 2353 | 47 | 98.04% | 0.28% |
| 180 | 2264 | 90 | 96.23% | 0.39% | 2316 | 84 | 96.50% | 0.38% |
| 365 | 2209 | 103 | 95.68% | 0.42% | 2285 | 115 | 95.21% | 0.44% |
| 725 | 2024 | 126 | 94.63% | 0.47% | 1552 | 160 | 93.04% | 0.53% |
| 1085 | 1729 | 166 | 92.63% | 0.55% | 798 | 194 | 90.35% | 0.69% |
Clinical Outcomes for DuraGraft Registry vs Published Literature
The sponsor conducted a literature review of published registries to gain further perspective on the observed outcomes in the single-arm DuraGraft Registry. Outcomes evaluated at 30 days and 1 year included all-cause mortality and the components of MACE versus the published literature using EuroSCORE II values for comparison. Values are presented in the table when reported in each study.
11
Mortality data for the DuraGraft Registry is comparable to contemporary registry studies, which reported 30-day and/or in-hospital mortality for patients undergoing isolated CABG surgery as seen in Table 6. The 30-day death rate was 2.3% in the DuraGraft Registry and ranged from 1.1% in Bangalore et alb to 3.2% in Adelborg et al7. It is notable that the comparative registries mostly reported in-hospital mortality. One-vear mortality in real world registry studies ranged from 4.8% in the MAIN COMPARE® registry to 10.5% in Biancari et al9, compared to 4.5% in the DuraGraft Registry.
| Surgery - Registry Studies | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| European Registries | Non-European Registries | ||||||||
| Study | DuraGraft | ||||||||
| Registry | Paparella | ||||||||
| (2014)10 | Biancari | ||||||||
| (2012)9 | Kieser | ||||||||
| (2016)11 | Adelborg | ||||||||
| (2017)7 | Beckman | ||||||||
| (2019)11 | Bangalore | ||||||||
| (2015)6 | MAIN- | ||||||||
| COMPARE | |||||||||
| (2008)8 | Puskas | ||||||||
| (2012)12 | |||||||||
| Number of CABG | |||||||||
| patients | 2,544 | 2,605 | 1,027 | 1,125 | 47,415 | 34,224 | 9,223 | 542 | 20,014 |
| EuroSCORE (II) | 2.3% ± 3.4 | 4.5% ± 6.7 | 1.5% | ||||||
| Syntax score | |||||||||
| 30 days or In- | |||||||||
| Hospital | 30 days | In- | |||||||
| hospital | 30 days | In- | |||||||
| hospital | 30 days | In hospital | 30 days + | ||||||
| in-hospital | 30 days | ||||||||
| Death | 2.3% | 3% | 3.7% | 3.2% | 3.2% | 2.7% | |||
| (3% OPCAB) | 1.1% | 2.1% | |||||||
| Cardiac death | 2.3% | 1.4% | |||||||
| Non cardiovascular | 0.0% |
2.4%
1 year
10.5%
0 4%
1 2%
I vear
4.8%
1 5%
I year
5.49
| Table 6. 30-Day and 1-Year Comparative MACE Event Rates in Patients Receiving Isolated CABG | ||
|---|---|---|
| Surgery - Registry Studies |
Pediatric Extrapolation
1.3%
1.3%
1.596
1 year
4.506
2196
2546
2156
In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.
I year
6.03
References
M
I vear
Death
Stroke
MI
Revascularization
Bevascularization
1 Pachuk CJ. Rushton-Smith SK. Emmert MY. Intraoperative storage of saphenous yein grafts in coronary bypass grafting. Expert Review of Medical Devices, 2019
2 Korkmaz-Icoz S, Ballikaya B, Soethoff J, et al, Graft Preservation Solution DuraGraft Alleviates Vascular Dysfunction Following In Vitro Ishemia/Reperfusion Injury in Rats. Pharmaceuticals 2021 doi: 10.3390/ph14101028
3 Aschacher T., Baranyl U., Aschacher O. et al. A Novel Endothelial Damage Inhibitor Reducers Oxidative Stress and Improves Cellular Integrity in Radial Artery Grafts for Coronary Artery Bypass. Frontiers in CV Med. 2021; 8:1-12.
4 Perrault LP, Carrier M, Voisine P, Olsen PS, Noiseux N, Jeanmart H, Cardemartiri F, Veerasingam D, Brown C, Guertin MC, Satishchandran V, Goeken T, Emmert MY. Sequential multidetector computed tomography assessments after venous graft treatment solution in coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2019 Nov 9:S0022-5223(19)32503-6. doi: 10.1016/j.jtcvs.2019.10.115.
5 Caliskan E. Sandner S. Misfeld M. Aramendi J. Salzberg SP. Choi YH. Satishchandran V. Iyer G. Perrault LP, Böning A. Emmert MY. A novel endothelial damage inhibitor for the treatment of vascular conduits in coronary artery bypass grafting; protocol and rationale for the European,
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multicentre, prospective, observational DuraGraft registry. J Cardiothorac Surg. 2019 Oct 15:14(1):174.
6 Bangalore, Sripal, et al. "Everolimus-eluting stents or bypass surgery for multivessel coronary disease." New England Journal of Medicine 372.13 (2015): 1213-1222.
7 Adelborg, Kasper, et al. "Thirtv-year mortality after coronary artery bypass graft surgery: a Danish nationwide population-based cohort study." Circulation: Cardiovascular Quality and Outcomes 10.5 (2017): e002708.
8 Seung, Ki Bae, et al. "Stents versus coronary-artery bypass grafting for left main coronary artery disease." New England Journal of Medicine 358.17 (2008): 1781-1792.
9 Biancari, Fausto, et al. "Validation of EuroSCORE II in patients undergoing coronary artery bypass surgery." The Annals of thoracic surgery 93.6 (2012): 1930-1935.
10 Paparella, Domenico, et al. "Risk stratification for in-hospital mortality after cardiac surgery: external validation of EuroSCORE II in a prospective regional registry." European journal of cardio-thoracic surgery 46.5 (2014): 840-848.
11 Kieser, Teresa M., M. Sarah Rose, and Stuart J. Head. "Comparison of logistic EuroSCORE and EuroSCORE II in predicting operative mortality of 1125 total arterial operations." European Journal of Cardio-Thoracic Surgery 50.3 (2016): 509-518.
12 Beckmann, Andreas, et al. "German heart surgery report 2018: the annual updated registry of the German Society for Thoracic and Cardiovascular Surgery." The Thoracic and cardiovascular surgeon 67.05 (2019): 331-344.
13 Puskas, John D., et al. "The society of thoracic surgeons 30-day predicted risk of mortality score also predicts long-term survival." The Annals of thoracic surgery 93.1 (2012): 26-35.
LABELING
The sponsor provided labeling that included the instructions for use and package labels. The labeling includes instructions intended to minimize the risk of improper use of the DuraGraft device. The labeling also includes a summary of the non-clinical performance testing that supports use of the device as a flushing and storage solution for vascular autografts.
Important components of the labeling include:
A description of the intended patient population, age, and condition. DuraGraft is indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts.
Saphenous vein grafts may be stored in DuraGraft for up to 4 hours.
DuraGraft Vascular Conduit Solution includes a component. L-arginine. L-arginine may cause an allergic reaction in certain patients.
DuraGraft is not intended for direct injection or intravenous infusion.
Prior to use, each container should be checked for leaks and particulate matter. If a leak, particulate matter, precipitates, or contamination are evident in the solution, the product should be discarded.
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The re-use of this product is hazardous to patient safety and may cause serious infections from contamination of opened product, leading to serious injury or death.
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of the flushing and storage solution for vascular autografts at room temperature and the measures necessary to mitigate these risks.
| Risks to Health | Mitigation Measures |
|---|---|
| Adverse tissue reaction | Biocompatibility evaluation |
| Damage to vascular grafts leading to | |
| major adverse cardiac events or | |
| vascular injury | Clinical performance data |
| Non-clinical performance testing | |
| Shelf life testing | |
| Labeling | |
| Particulate matter contamination | |
| leading to vascular occlusion, | |
| coronary artery embolization and | |
| occlusion, phlebitis, infarction, and | |
| death | Clinical performance data |
| Non-clinical performance testing | |
| Shelf life testing | |
| Labeling | |
| Infection | Sterilization validation |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, the flushing and storage solution for vascular autografts at room temperature is subject to the following special controls:
- (1) Clinical data must evaluate adverse events associated with clinical use of the device. Devices indicated for vascular grafts for coronary artery bypass graft surgeries must include an evaluation of the incidence of major adverse cardiac events, vein graft occlusion, and mortality.
- Non-clinical performance testing must demonstrate that the device performs as (2) intended under anticipated conditions of use. The following performance characteristics must be tested:
- Maintenance of cell viability and structural integrity of vascular conduits during (i) storage at the labeled temperature and storage duration: and
- (ii) Evaluation of visible and non-visible particulates in the final mixed solution.
- (3) Shelf life testing must demonstrate the stability of the device's chemical components over the identified shelf life.
- The device must be demonstrated to be biocompatible. (4)
- (ર) Performance data must demonstrate the sterility of the device.
- (6) Labeling must include:
- The maximum storage duration for vascular autografts in the solution; (i)
- A description of all additives or supplements that are added at the point of care; (ii)
- (iii) The need for visual inspection of the solution for particulate matter prior to use;
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- (iv) A statement regarding the duration of stability of the final solution after preparation:
- A summary of the non-clinical performance testing that supports use of the (v) device as a flushing and storage solution for vascular autografts; and
- (vi) A summary of the clinical data that supports use of the device as a flushing and storage solution for vascular autografts.
BENEFIT-RISK DETERMINATION
The risks to health of a flushing and storage solution for vascular autografts can generally include adverse tissue reaction, damage to the vascular graft leading to major adverse cardiac events or vascular injury, and clinical risk of particulate matter contamination including vascular occlusion, coronary artery embolization and occlusion, phlebitis, infarction, and death. However, there is no evidence from the preclinical and clinical studies of any adverse events related to the DuraGraft Vascular Conduit Solution. The preclinical testing for the DuraGraft Vascular Conduit Solution demonstrated that these risks are adequately mitigated by biocompatibility testing, non-clinical performance testing, and clinical performance testing. The device safety is supported by data collected in the clinical studies described above. The sponsor provided short-term and follow-up data up to 1 year from an ongoing all-comers European prospective registry of patients who received DuraGraft-treated vascular grafts as a postapproval study for CE Mark in Europe. A total of 2,964 patients were enrolled in the Registry, between December 2016 and August 2019, at 45 centers in eight countries. Following a comprehensive review of the literature, the sponsor compared Major Adverse Cardiac Events (MACE) and the individual components that make up MACE (e.g., death, myocardial infarction and repeat MI) from the registry to contemporary literature derived from trials of CABG surgery. The 30-day death rate was 2.3% in the DuraGraft Registry and ranged from 1.1% to 3.2% in the cited references. The observed mortality of 4.5% at one year is comparable to rates reported in multiple clinical trials, which range from 2.7% to 7.5%. In the isolated CABG registry, the 30 day and 1-year all-cause mortality are within the range of what has been reported in the literature for comparable patient populations. The incidence for myocardial infarction and revascularization were also within the same range. The DuraGraft Registry includes 2,522 patients who underwent Isolated CABG surgery. An additional comparison was made to select propensity matched cohorts of patients from the STS database and evaluate all-cause mortality between the matched cohorts at 30 days, 1 year, and 3 years of follow-up.
The review of these clinical studies is supportive of the device safety; however, there is no clear clinical evidence that the device is more effective compared to the standard of care. In a prospective randomized self-control study, the sponsor demonstrated favorable effects related to the use of DuraGraft on saphenous vein wall thickness compared to standard of care. A radiographic assessment of the saphenous vein grafts at 12 months by multidetector computed tomography (MDCT) evaluation showed reduced wall thickness in DuraGraft-treated saphenous vein grafts compared to standard of care treated saphenous vein grafts. However, there is no evidence that this biomarker can serve as a surrogate for long term vein graft patency.
The probable benefits of the device are based on nonclinical laboratory studies described above to support the device use as a flushing and storage solution for saphenous vein grafts at room
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temperature for up to 4 hours. Non-clinical performance testing demonstrated that human saphenous vein segments and pig mammary vein segments that were flushed and stored in DuraGraft for time points ranging from 15 minutes to 24 hours exhibited increased graft cell viability and improved maintenance of graft endothelial morphology compared to vein segments that were stored in normal saline solution.
Additionally, as there is no alternative legally marketed solution for the short-term flushing and storage of saphenous vein grafts during CABG surgery, the device addresses an unmet need.
Patient Perspectives
This submission did not include specific information on patient perspectives for this device.
Benefit/Risk Conclusion
In conclusion, given the available information above, for the following indication statement:
DuraGraft Vascular Conduit Solution is a solution indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts from harvesting through grafting for up to 4 hours.
The probable benefits outweigh the probable risks for the DuraGraft Vascular Conduit Solution device. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.
CONCLUSION
The De Novo request for DuraGraft Vascular Conduit Solution is granted and the device is classified as follows:
Product Code: OEJ Device Type: Flushing and storage solution for vascular autografts at room temperature Regulation Number: 21 CFR 876.4100 Class: II