Peripheral Arterial Occlusive Disease
Conditions
Brief summary
To demonstrate the patency and safety of vascular grafts: EXXCEL and FUSION Bioline.
Detailed description
The study is a prospective, randomized, single-blind, two-arm, parallel group, multi-center study to evaluate the safety and efficacy of FUSION™ Vascular Graft with Bioline (heparin) coating, compared with EXXCEL Soft ePTFE in a peripheral bypass setting, to support a claim of substantial equivalence.
Interventions
DEVICEvascular grafts
All devices will be used to treat patients with peripheral arterial occlusive disease
Sponsors
Maquet Cardiovascular
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
This was a single-blind study. The surgeon and study site staff knew which vascular graft each subject received, but the subject did not.
Intervention model description
This was a prospective, randomized, single-blind (subject), parallel group, multicenter study in subjects with peripheral arterial occlusive disease (PAOD) who were scheduled to undergo femoral popliteal peripheral bypass surgery. Eligible subjects were randomly assigned in a 1:1 ratio to receive either FUSION Bioline or EXXCEL vascular graft.
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient required either above-knee or below-knee femoral popliteal bypass; * Patient had Category 1, 2, 3 4 or 5 chronic limb ischemia as defined by the Rutherford Categories - chronic limb ischemia severity classification scale. * Patient was at least 21 years of age; * Patient had postoperative life expectancy of \>18 months; * Patient was willing and able to have follow-up visits and examinations; * Patient would not participate in other clinical trials that would conflict with this protocol * Patient was willing and able to provide written, informed consent.
Exclusion criteria
* Patient had a previous history of bypass in the diseased extremity (below the iliacs arteries); * Patient had percutaneous transluminal angioplasty or stenting of the target femoral or popliteal artery at the anticipated site of the proximal or distal anastomosis within the previous 30 days; * Patient had active infection in the region of graft placement; * Patient had an acute arterial occlusion requiring an emergent intervention; * Patient needed a cardiac surgical procedure or a different vascular surgical procedure within 30 days of planned lower extremity revascularization. Planned endovascular procedures to address proximal stenotic lesions at the time of the index femoropopliteal bypass did not exclude a patient from the study; * Patient required sequential extremity revascularizations or other procedures that require use of additional vascular grafts; * Patient had known hypersensitivity or contraindication to aspirin; * Patient had known coagulation disorders including hypercoagulability; * Patient had previous instance of heparin-induced thrombocytopenia type 2 or has known hypersensitivity to heparin; Patient was currently treated with Coumadin (warfarin) that had not been stopped within 72 hours of the planned procedure * Patient had severe chronic renal insufficiency (plasma/serum creatinine \> 2.5 mg/dl), is undergoing hemodialysis. * Patient had prior renal transplant; * Patient had a stroke or myocardial infarction within 6 weeks of the procedure or had evidence of prior massive stroke (Modified Rankin Scale 3 or above); * Patient had a myocardial infarction within 6 weeks prior to the procedure or had unstable angina pectoris; * Patient had documented acute or suspected systemic infection; * Patient was a woman of reproductive potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Primary Patency | 6 months | A graft was considered to have primary patency if it had remained continuously patent (i.e., had continued blood flow through it) from the time of implantation and it had uninterrupted patency with no procedure performed on it, nor a procedure to address disease progression in the adjacent native vessel. Stenosis developing within the graft without remediation or occlusion was not considered a loss of primary patency. Assessed by duplex ultrasound imaging and ankle brachial index (ABI). |
| The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | 6 months | The composite endpoint included any of the following: * Major amputation - amputation that resulted in limb shortening (e.g., proximal to, but not including transmetatarsal amputations); * Major graft reintervention - placement of a new bypass graft at the same anatomic site, a jump/interposition graft, graft thrombectomy, graft excision, or graft thrombolysis; * Procedure-related death - any death within 30 days of the index procedure or within 30 days of any remedial procedure performed at the same anatomic site or as a result of the index procedure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Secondary Patency | 6 months | Secondary patency was defined as patency after some form of intervention to restore and maintain blood flow after occlusion. |
| Number of Participants With Primary Assisted Patency | 6 months | Primary assisted patency was defined as continued patency without thrombosis, with or without an endovascular or open surgical intervention to remediate a stenosis or other disorder of the graft. |
| Time to Hemostasis of Suture Hole Bleeding (Min) | Post-procedure | Time from the release of clamps until hemostasis, where hemostasis is defined as the absence of detectable bleeding from any of the suture holes. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Primary Assisted Patency | 30 days | Primary assisted patency was defined as continued patency without thrombosis, with or without an endovascular or open surgical intervention to remediate a stenosis or other disorder of the graft. |
| Number of Participants With Secondary Patency | 30 days | Secondary patency was defined as patency after some form of intervention to restore and maintain blood flow after occlusion. |
| Number of Participants With Primary Patency | 30 days | A graft was considered to have primary patency if it had remained continuously patent (i.e., had continued blood flow through it) from the time of implantation and it had uninterrupted patency with no procedure performed on it, nor a procedure to address disease progression in the adjacent native vessel. Stenosis developing within the graft without remediation or occlusion was not considered a loss of primary patency. |
Countries
Czechia, Germany, United States
Participant flow
Recruitment details
Recruitment period was from May 2010 to June 2012 at 18 sites in the United States (US) and 7 sites outside the US.
Pre-assignment details
Subjects (209) were randomly assigned to FUSION Bioline (108) or EXXCEL (101) - 2 subjects in the FUSION Bioline group did not undergo surgery and are excluded from all analysis. One (1) of 207 treated subjects was included in efficacy analysis but excluded from safety analysis due to wrong treatment (FUSION instead of FUSION Bioline implanted).
Participants by arm
| Arm | Count |
|---|---|
| EXXCEL Soft Patients who were enrolled and treated with the EXXCEL Soft vascular graft. | 100 |
| FUSION Bioline Patients who were enrolled and treated with the FUSION Bioline vascular graft. | 103 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 4 |
| Overall Study | Graft no longer evaluable | 9 | 9 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | FUSION Bioline | EXXCEL Soft |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 101 Participants | 60 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 102 Participants | 43 Participants | 59 Participants |
| Age, Continuous | 64.7 years STANDARD_DEVIATION 8.71 | 65.7 years STANDARD_DEVIATION 8.57 | 63.6 years STANDARD_DEVIATION 8.76 |
| Ankle Brachial Index (ABI) | 0.55 Ratio STANDARD_DEVIATION 0.22 | 0.55 Ratio STANDARD_DEVIATION 0.24 | 0.56 Ratio STANDARD_DEVIATION 0.21 |
| Baseline medications Angiotensin-converting enzyme (ACE) inhibitor | 172 Participants | 81 Participants | 91 Participants |
| Baseline medications Any antiplatelet | 12 Participants | 8 Participants | 4 Participants |
| Baseline medications Aspirin | 172 Participants | 87 Participants | 85 Participants |
| Baseline medications Clopidogrel | 28 Participants | 13 Participants | 15 Participants |
| Baseline medications Statin | 129 Participants | 67 Participants | 62 Participants |
| Baseline medications Warfarin | 7 Participants | 3 Participants | 4 Participants |
| Body Mass Index (BMI) | 27.7 kg/m^2 STANDARD_DEVIATION 4.85 | 27.7 kg/m^2 STANDARD_DEVIATION 4.86 | 27.8 kg/m^2 STANDARD_DEVIATION 4.85 |
| Comorbidities Arrhythmia | 19 Participants | 11 Participants | 8 Participants |
| Comorbidities Bleeding disorder | 2 Participants | 2 Participants | 0 Participants |
| Comorbidities Cerebrovascular event | 19 Participants | 7 Participants | 12 Participants |
| Comorbidities Chronic obstructive lung disease | 40 Participants | 24 Participants | 16 Participants |
| Comorbidities Congestive heart failure | 10 Participants | 6 Participants | 4 Participants |
| Comorbidities Coronary artery disease | 73 Participants | 38 Participants | 35 Participants |
| Comorbidities Diabetes mellitus | 72 Participants | 38 Participants | 34 Participants |
| Comorbidities Hyperlipidemia/hypercholesterolemia | 143 Participants | 71 Participants | 72 Participants |
| Comorbidities Hypertension | 174 Participants | 84 Participants | 90 Participants |
| Comorbidities Liver disease | 13 Participants | 6 Participants | 7 Participants |
| Comorbidities Obesity | 52 Participants | 25 Participants | 27 Participants |
| Comorbidities Previous myocardial infarction | 43 Participants | 21 Participants | 22 Participants |
| Comorbidities Previous target limb intervention | 51 Participants | 22 Participants | 29 Participants |
| Comorbidities Renal failure/dysfunction | 11 Participants | 8 Participants | 3 Participants |
| Comorbidities Varicose veins | 37 Participants | 20 Participants | 17 Participants |
| Graft diameter 6 mm | 97 Participants | 48 Participants | 49 Participants |
| Graft diameter 8 mm | 106 Participants | 55 Participants | 51 Participants |
| Height | 171.8 cm STANDARD_DEVIATION 9.2 | 171.2 cm STANDARD_DEVIATION 10.2 | 172.5 cm STANDARD_DEVIATION 8.1 |
| Leg treated Left | 106 Participants | 53 Participants | 53 Participants |
| Leg treated Right | 97 Participants | 50 Participants | 47 Participants |
| Race/Ethnicity, Customized African American | 10 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 190 Participants | 98 Participants | 92 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Czechia | 127 participants | 63 participants | 64 participants |
| Region of Enrollment Germany | 9 participants | 5 participants | 4 participants |
| Region of Enrollment United States | 67 participants | 35 participants | 32 participants |
| Rutherford Category 1-3 (claudication) | 147 Participants | 71 Participants | 76 Participants |
| Rutherford Category 4-5 (limb threat) | 56 Participants | 32 Participants | 24 Participants |
| Sex: Female, Male Female | 58 Participants | 30 Participants | 28 Participants |
| Sex: Female, Male Male | 145 Participants | 73 Participants | 72 Participants |
| Site of distal anastomosis Above knee | 174 Participants | 88 Participants | 86 Participants |
| Site of distal anastomosis Below knee | 28 Participants | 14 Participants | 14 Participants |
| Site of distal anastomosis Other | 1 Participants | 1 Participants | 0 Participants |
| Site of proximal anastomosis Common femoral | 193 Participants | 99 Participants | 94 Participants |
| Site of proximal anastomosis External iliac | 4 Participants | 2 Participants | 2 Participants |
| Site of proximal anastomosis Other | 1 Participants | 0 Participants | 1 Participants |
| Site of proximal anastomosis Profunda femoral | 1 Participants | 0 Participants | 1 Participants |
| Site of proximal anastomosis Superficial femoral | 4 Participants | 2 Participants | 2 Participants |
| Tobacco use Current smoker | 105 Participants | 54 Participants | 51 Participants |
| Tobacco use Non-smoker | 35 Participants | 18 Participants | 17 Participants |
| Tobacco use Prior smoker | 63 Participants | 31 Participants | 32 Participants |
| Weight | 82.2 kg STANDARD_DEVIATION 16.99 | 81.4 kg STANDARD_DEVIATION 17.06 | 83.1 kg STANDARD_DEVIATION 16.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 101 | 4 / 105 |
| other Total, other adverse events | 14 / 101 | 24 / 105 |
| serious Total, serious adverse events | 50 / 101 | 44 / 105 |
Outcome results
Primary
Number of Participants With Primary Patency
A graft was considered to have primary patency if it had remained continuously patent (i.e., had continued blood flow through it) from the time of implantation and it had uninterrupted patency with no procedure performed on it, nor a procedure to address disease progression in the adjacent native vessel. Stenosis developing within the graft without remediation or occlusion was not considered a loss of primary patency. Assessed by duplex ultrasound imaging and ankle brachial index (ABI).
Time frame: 6 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Patency | 70 Participants |
| FUSION Bioline | Number of Participants With Primary Patency | 89 Participants |
Comparison: It was calculated that 200 participants randomized in a 1:1 fashion would have at least 80% power to detect a difference of 15% in the number of participants with primary patency between FUSION Bioline and EXXCEL groups at 6 months. It was assumed that the ratio of Above-Knee to Below-Knee procedures was 60:40; based on this, the primary patency rate for the combined Above-Knee and Below-Knee patients was 79%. Assumptions included a 10% withdrawal rate prior to the 6-month evaluation.p-value: <0.000195% CI: [2.7, 29.9]Exact 1-sided test
Primary
The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD)
The composite endpoint included any of the following: * Major amputation - amputation that resulted in limb shortening (e.g., proximal to, but not including transmetatarsal amputations); * Major graft reintervention - placement of a new bypass graft at the same anatomic site, a jump/interposition graft, graft thrombectomy, graft excision, or graft thrombolysis; * Procedure-related death - any death within 30 days of the index procedure or within 30 days of any remedial procedure performed at the same anatomic site or as a result of the index procedure.
Time frame: 6 months
Population: Safety population, defined as all randomized subjects who received the FUSION Bioline or EXXCEL vascular graft, analyzed according to the treatment they received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EXXCEL Soft | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Major amputation | 2 Participants |
| EXXCEL Soft | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Major graft reintervention | 31 Participants |
| EXXCEL Soft | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Procedure-related death | 1 Participants |
| EXXCEL Soft | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Any MALE or POD | 31 Participants |
| FUSION Bioline | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Any MALE or POD | 18 Participants |
| FUSION Bioline | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Major amputation | 5 Participants |
| FUSION Bioline | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Procedure-related death | 1 Participants |
| FUSION Bioline | The Number of Participants Meeting Composite Endpoint of Major Adverse Limb Events (MALE) and Periprocedural Death (POD) | Major graft reintervention | 17 Participants |
Comparison: The number and percentage of subjects with a MALE or POD event were summarized by treatment group.p-value: 0.033Fisher Exact
Secondary
Number of Participants With Primary Assisted Patency
Primary assisted patency was defined as continued patency without thrombosis, with or without an endovascular or open surgical intervention to remediate a stenosis or other disorder of the graft.
Time frame: 6 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Assisted Patency | 73 Participants |
| FUSION Bioline | Number of Participants With Primary Assisted Patency | 89 Participants |
p-value: 0.017Chi-squared
Secondary
Number of Participants With Secondary Patency
Secondary patency was defined as patency after some form of intervention to restore and maintain blood flow after occlusion.
Time frame: 6 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Secondary Patency | 80 Participants |
| FUSION Bioline | Number of Participants With Secondary Patency | 91 Participants |
p-value: 0.137Chi-squared
Secondary
Time to Hemostasis of Suture Hole Bleeding (Min)
Time from the release of clamps until hemostasis, where hemostasis is defined as the absence of detectable bleeding from any of the suture holes.
Time frame: Post-procedure
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXXCEL Soft | Time to Hemostasis of Suture Hole Bleeding (Min) | 11 minutes | Standard Deviation 10.63 |
| FUSION Bioline | Time to Hemostasis of Suture Hole Bleeding (Min) | 3.5 minutes | Standard Deviation 4.72 |
Comparison: Difference between groups were compared with the Wilcoxon Rank Sum Testp-value: <0.0001Wilcoxon (Mann-Whitney)
Other Pre-specified
Number of Participants With Primary Assisted Patency
Primary assisted patency was defined as continued patency without thrombosis, with or without an endovascular or open surgical intervention to remediate a stenosis or other disorder of the graft.
Time frame: 30 days
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Assisted Patency | 87 Participants |
| FUSION Bioline | Number of Participants With Primary Assisted Patency | 96 Participants |
Other Pre-specified
Number of Participants With Primary Assisted Patency
Primary assisted patency was defined as continued patency without thrombosis, with or without an endovascular or open surgical intervention to remediate a stenosis or other disorder of the graft.
Time frame: 12 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months. The 12 month efficacy analysis population for the 12 month results included those subjects who met the study endpoint at both 6 and 12 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Assisted Patency | 67 Participants |
| FUSION Bioline | Number of Participants With Primary Assisted Patency | 76 Participants |
p-value: 0.181Chi-squared
Other Pre-specified
Number of Participants With Primary Patency
A graft was considered to have primary patency if it had remained continuously patent (i.e., had continued blood flow through it) from the time of implantation and it had uninterrupted patency with no procedure performed on it, nor a procedure to address disease progression in the adjacent native vessel. Stenosis developing within the graft without remediation or occlusion was not considered a loss of primary patency.
Time frame: 30 days
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Patency | 87 Participants |
| FUSION Bioline | Number of Participants With Primary Patency | 96 Participants |
Other Pre-specified
Number of Participants With Primary Patency
A graft was considered to have primary patency if it had remained continuously patent (i.e., had continued blood flow through it) from the time of implantation and it had uninterrupted patency with no procedure performed on it, nor a procedure to address disease progression in the adjacent native vessel. Stenosis developing within the graft without remediation or occlusion was not considered a loss of primary patency.
Time frame: 12 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months. The 12 month efficacy analysis population for the 12 month results included those subjects who met the study endpoint at both 6 and 12 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Primary Patency | 65 Participants |
| FUSION Bioline | Number of Participants With Primary Patency | 75 Participants |
p-value: 0.000195% CI: [-4.8, 23]Exact 1-sided test
Other Pre-specified
Number of Participants With Secondary Patency
Secondary patency was defined as patency after some form of intervention to restore and maintain blood flow after occlusion.
Time frame: 30 days
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Secondary Patency | 92 Participants |
| FUSION Bioline | Number of Participants With Secondary Patency | 97 Participants |
Other Pre-specified
Number of Participants With Secondary Patency
Secondary patency was defined as patency after some form of intervention to restore and maintain blood flow after occlusion.
Time frame: 12 months
Population: Subset of the efficacy analysis population with available data for analysis. The efficacy analysis population included all randomized subjects who met a study endpoint at 6 months. The 12 month efficacy analysis population for the 12 month results included those subjects who met the study endpoint at both 6 and 12 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EXXCEL Soft | Number of Participants With Secondary Patency | 77 Participants |
| FUSION Bioline | Number of Participants With Secondary Patency | 80 Participants |
p-value: 0.68Chi-squared