Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00496639 |
| Other study ID # |
YIG482 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
July 3, 2007 |
| Last updated |
May 21, 2008 |
| Start date |
October 2006 |
| Est. completion date |
December 2010 |
Study information
| Verified date |
May 2008 |
| Source |
National Kidney Foundation |
| Contact |
Ivan D Maya, MD |
| Phone |
205-996-2186 |
| Email |
imaya[@]uab.edu |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
Arteriovenous grafts are used as the vascular access in 40-50% of hemodialysis patients.
Grafts are prone to recurrent stenosis (narrowing) and thrombosis (clotting). Graft clotting
is usually due to a narrowing at the site where the graft joins the vein. The standard
treatment is to remove the clot and angioplasty the narrowed area. The long-term outcome is
not good, lasting only about 1 month. Placing a stent (a small metallic, PTFE covered,
spring) at the narrowed site may keep the graft open longer. Principal investigator's
preliminary research data suggest that placing a stent at the stenotic site prolongs graft
patency following thrombectomy, as compared to conventional angioplasty.
This is a single-center, randomized clinical trial, in which patients with a clotted graft
with underlying stenosis at the venous anastomosis of the graft will be allocated to
thrombectomy + angioplasty (control group) or to thrombectomy + stent placement (study
group). The primary endpoint will be primary (unassisted) graft patency. The secondary
endpoints will be secondary (assisted) graft patency and overall access-related costs.
Description:
HYPOTHESES
1. The primary patency of grafts following thrombectomy and angioplasty is limited by the
high re-stenosis rate.
2. Stent deployment reduces the likelihood of re-stenosis at the site of the stenotic
lesion, thereby prolonging primary graft patency following thrombectomy, and decreasing
or delaying the need for future interventions.
3. The cost savings arising from stent deployment (decrease in subsequent access
procedures) outweigh the additional cost of the stent itself.
AIMS
1. To evaluate whether stent placement in thrombosed grafts with underlying stenosis at
the venous anastomosis results in longer primary graft patency, as compared with
angioplasty alone.
2. To determine whether stent placement in thrombosed grafts with underlying stenosis at
the venous anastomosis reduces the subsequent cost of access procedures in excess of
the cost of the stent.
To accomplish these goals, we will conduct a randomized clinical trial of hemodialysis
patients who are referred for treatment of thrombosed A-V grafts. The patients will be
randomized to be treated with thrombectomy + stent deployment or thrombectomy + angioplasty.
The primary outcomes will be primary (unassisted) graft patency. The secondary outcomes will
be secondary (assisted) graft patency and the cumulative cost of all access-related
procedures, hospitalizations, and complications.
SIGNIFICANCE AND BACKGROUND
Most patients with end-stage renal disease undergo hemodialysis thrice weekly to optimize
their survival, minimize medical complications, and enhance their quality of life. A
reliable vascular access is a critical requirement for providing adequate hemodialysis. The
ideal vascular access would be easy to place, ready to use as soon as it is placed, deliver
high blood flows indefinitely, and be free of complications. None of the existing types of
vascular accesses achieve this ideal. Among the three types of vascular access currently
available, A-V fistulas are superior to A-V grafts, which in turn are superior to dialysis
catheters. Recognizing the relative merits of the vascular access types, the NKF-DOQI
guidelines recommend placement of A-V fistulas in 50% of hemodialysis patients, A-V grafts
in 40%, and dialysis catheters in 10% [19]. The actual current distribution of vascular
accesses among prevalent hemodialysis patients in the United States is 25-30% fistulas,
45-50% grafts, and 25% dialysis catheters [20, 21]. Vascular access procedures and their
subsequent complications represent a major cause of morbidity, hospitalization and cost for
chronic hemodialysis patients [22-26]. Over 20% of hospitalizations in hemodialysis patients
in the United States are access-related, and the annual cost of access morbidity is close to
$1 billion [25].
A-V grafts are more prone to recurrent stenosis and thrombosis than are fistulas, and
require multiple radiologic or surgical interventions to ensure their long-term patency for
dialysis [26]. A report from UAB observed that the first salvage procedure to maintain graft
patency (thrombectomy, angioplasty, or surgical revision) was required in 29% of grafts at 3
months, 52% at 6 months, 77% at 12 months, and 96% at 24 months [5]. Most grafts required
multiple interventions over time to maintain their patency for dialysis. A mean of 1.22
interventions were required to maintain access patency per graft-year, including 0.51
thrombectomies, 0.54 angioplasties, and 0.17 surgical revisions. Secondary graft survival
(time from initial placement to permanent failure, regardless of number of interventions)
has ranged from 59 to 87% at one year, and 50 to 73% at two years [27-35]. A number of
studies have examined the association of demographic and clinical factors with long-term
graft survival, but no consistent clinical predictor of poor graft outcome has emerged.
Windus et al [27] observed lower graft survival in diabetics as compared with nondiabetics.
In contrast, three other studies observed no significant difference in graft survival
between diabetic and nondiabetic patients [5, 35, 36]. Several investigators have reported a
lack of association between patient age or sex and long-term graft survival [5, 35-37].
Windus et al [27] found that older age predicted lower graft survival in non-diabetics, but
not in diabetic patients. Graft survival is similar between upper arm and forearm grafts [5,
29]. Finally, hypoalbuminemia has been associated with shorter A-V graft survival in 2
reports [5, 36].
The major cause of graft failure is thrombosis due to underlying stenosis of the venous
anastomosis, draining vein, or central vein [10, 38]. When the stenosis is not detected and
corrected in a timely fashion, grafts typically thrombose. Clotted grafts require
thrombectomy by either Radiology or Surgery, most commonly in association with correction of
the underlying stenosis. If graft patency cannot be restored, it becomes necessary to
construct a vascular access at a new anastomotic site. Intervention-free graft patency is
considerably lower following thrombectomy than after elective angioplasty [10]. A comparison
of graft outcomes after radiologic interventions at our institution found that the primary
(unassisted) patency was only 30% at 3 months for clotted grafts, as compared with 71% for
patent grafts undergoing elective angioplasty [10]. Not surprisingly, graft survival was
worse if there was a residual stenosis after the angioplasty. However, even in the subset of
patients with no residual stenosis after the intervention, the primary 3-month patency was
still lower in clotted grafts, as compared with patent grafts undergoing elective
angioplasty (median survival, 2.5 vs 6.9 months).
Because graft patency is much worse following thrombectomy than after elective angioplasty,
the current state of clinical access management involves an ongoing surveillance program to
monitor for evidence of hemodynamically significant graft stenosis, and referral of such
patients for elective angioplasty or surgical revision. The rationale for this approach is
that correction of graft stenosis in a timely fashion will decrease the risk of graft
thrombosis and prolong the survival of the graft [19]. Substantial clinical research has
been directed at evaluating the predictive values of several noninvasive screening tests to
identify hemodynamically significant graft stenosis, so that the patients can be referred
for angioplasty or surgical revision before the graft has a chance to clot. These
surveillance methods have included: dynamic dialysis venous pressures, static dialysis
venous pressures, recirculation, Doppler ultrasound, ultrasound dilution methodology, and
access blood flow (Reviewed in [39]). Graft stenosis can also be predicted by aggressive
clinical monitoring (looking for decreases in Kt/V, prolonged bleeding at graft needle
sites, and abnormalities of graft inspection and auscultation [1, 40]. A number of
observational studies have reported substantial (50-60%) reductions in the frequency of
graft thrombosis using a variety of surveillance methods [40-43]; none have eliminated this
problem. Four randomized studies evaluating the efficacy of access surveillance on graft
outcomes have found that surveillance is an excellent tool for identifying hemodynamically
significant graft stenosis. However, the higher frequency of preemptive angioplasty in the
surveillance group did not appear to translate into a reduction in graft thrombosis or
prolongation of graft survival [44-47]. This discrepancy suggests that preemptive
angioplasty may not be effective in producing sustained improvement of the stenotic lesion.
Stent deployment may improve the durability of graft angioplasty and decrease the
variability between operators in graft patency following radiologic interventions. Thus, it
is possible that more frequent use of stents might enhance the value of graft surveillance.
Graft stenosis occurs as a consequence of aggressive myointimal hyperplasia, which occurs
most commonly at the venous anastomosis [48]. Vascular injury resulting from the angioplasty
may actually accelerate the process of myointimal hyperplasia, thereby resulting in early
re-stenosis [49]. Endoluminal stents, by forming a rigid scaffold at the venous anastomosis,
may slow the encroachment of the area of myointimal hyperplasia into the vascular lumen,
thereby limiting the magnitude of recurrent stenosis. Thus, use of stents may be of utility
in preventing restenosis following angioplasty. Stent placement has been attempted for
treatment of grafts in which angioplasty results in suboptimal technical success or if the
stenosis recurs rapidly. A number of small series have reported the outcomes of stent
placement for vascular access with refractory stenosis [50-56]. Unfortunately, these studies
have suffered from several methodologic limitations, including retrospective data
collection, absence of a suitable control group, combining patent and thrombosed grafts,
combining stents placed at a variety of stenotic sites, and combining grafts with fistulas.
A small, randomized study comparing stents with conventional angioplasty found no difference
in primary graft patency following the intervention [54]. However, this study enrolled a
mixture of clotted grafts and patent grafts, and the stenotic lesions were at a variety of
locations, limiting the interpretation of the findings. A recent, uncontrolled study
reported the outcomes of clotted grafts undergoing thrombectomy, as well as stent placement
at the venous anastomosis [50]. In this more homogeneous group of grafts, the primary graft
patency was 63% at 6 months. Although there was no matched control group treated with
angioplasty alone, the unassisted graft survival was far superior to that reported in
several series (11 to 34% at 6 months)[10, 57-61]
RESEARCH DESIGN AND METHODS
Design: This will be an open-label, prospective, randomized clinical trial comparing the
outcomes of thrombosed AV grafts treated with mechanical thrombectomy and angioplasty
(current standard of care), as compared with stent deployment after mechanical thrombectomy
and angioplasty.
Subjects: The subjects for this study will be recruited from the University of Alabama at
Birmingham (UAB) Nephrology practice. UAB provides medical care for approximately 500
hemodialysis patients, under the supervision of 12 full-time nephrologists. We average 150
graft thrombectomy procedures annually at our institution.
Methods:
Screening: After obtaining informed consent, the clinic chart will be reviewed for inclusion
and exclusion criteria. The subject will undergo a screening evaluation including a history
and physical prior to the intervention.
Randomization: All subjects with a recent thrombosed AV graft who meet the inclusion and
exclusion criteria and consent to participation in the study will be randomized to either
the angioplasty arm or the angioplasty plus stent deployment arm. Patients will be taken to
the interventional suite in the Interventional Radiology department. Randomization will
occur only after ascertaining that that graft flow has been restored and that there is a
>50% stenosis at the venous anastomosis. Randomization will be accomplished by unsealing a
sequentially numbered opaque envelope that contains the randomization allocation for that
subject.
Angioplasty Arm: These patients will undergo the standard of care protocol: mechanical
thrombectomy plus angioplasty of the stenosis at the venous anastomosis.
Stent Deployment Arm: These patients will undergo the same protocol as the angioplasty arm
but at the end a covered stent (wallgraft) will be deployed at the stenotic lesion of the
venous anastomosis.
Procedures:
Angioplasty Arm: All patients diagnosed with a thrombosed graft will undergo mechanical
thrombectomy within 48 hours of diagnosis in conjunction with angioplasty of the underlying
stenotic lesion. The grafts are initially accessed with a single needle at the arterial limb
of the graft. A glide wire is passed up to the central vessels and the needle exchanged for
a 6-French catheter sheath. Mechanical thrombectomy is achieved with a Trerotola device. A
second 6-French sheath is placed in the venous limb of the graft, and a glide wire passed
into the arterial circulation. A Fogarty balloon is passed through the wire beyond the
arterial anastomosis and pulled back to dislodge the clot. An anterograde and retrograde
angiogram of the graft is performed to assess patency and to look and grade the stenotic
lesions. Lesions at the venous anastomosis with at least 50% stenosis are considered
hemodynamically significant. An angioplasty balloon is placed and inflated at the level of
the stenotic site.
Stent Arm: The procedure will be identical to that followed in the angioplasty arm. However,
after the stenotic lesion has been angioplastied, the appropriate Bard Fluency-cPTFE
Encapsulated Nitinol Stent will be deployed.
All patients will receive 3000 to 4000 units of heparin during the procedure.
All patient receive conscious sedation with Fentanyl and Versed, unless allergic to either
one
In both randomized groups, a final angiogram of the graft will be performed, and the
residual stenosis at the site of the angioplasty quantified. In addition, intra-graft and
systemic blood pressures will be measured upon completion of the intervention. These
pressures will be measured directly through a disposable pressure transducer. The ratio of
graft to systemic systolic pressure will be calculated. This ratio has been previously shown
to be predictive of subsequent primary graft patency [1, 10].
Subsequent Intervention for Either Arm: Subsequent graft interventions will be determined by
the clinical judgment of the patient's nephrologists, independently of the study
intervention. Such intervention may include mechanical thrombectomy with angioplasty if the
graft re-thromboses; referral for diagnostic fistulogram with possible angioplasty if there
is clinical suspicion o graft stenosis; surgical revision if the graft has a stenosis that
is not amenable to radiologic intervention; and placement of a dialysis catheter if graft
patency cannot be restored. All these events will be tracked prospectively. Completeness of
information about subsequent access interventions will be optimized by a cross-check with
the Division of Nephrology prospective, computerized, access database maintained by our
Access Coordinators [40].
Endpoints. The primary end point will be the primary patency of the graft (time from the
initial thrombectomy to the next graft intervention (angioplasty, thrombectomy, or surgical
revision).
The secondary end points are:
1. Secondary patency, (time from thrombectomy to permanent graft failure, regardless of
number of subsequent salvage procedures)
2. Total cost of access procedures and access complications per year of followup.
Follow-up Period: Subjects will be followed for a period of 2 years from the date of
randomization. Prospective data will be collected on (1) all subsequent access procedures
(angioplasty, thrombectomy, surgical revision, or placement of dialysis catheter), (2) all
access-related hospitalizations (those due to an access complication or non-access related
hospitalizations in which an access procedure is performed), and (3) all access-related
complications, e.g., catheter-related bacteremia or metastatic infections.
Statistical Analysis:
Sample size: Power calculations were performed by the statistician (Jill Barker, Ph.D.) on
the basis of our preliminary data from the outcome of thrombosed grafts at UAB. The
estimated sample of 130 patients, evenly divided between the two groups, was sufficient to
detect a tripling in median graft survival from 1 month on the control arm to 3 months on
the stent arm, assuming an exponential distribution, 3 years of accrual, 1 year of followup,
two-sided significance level of 0.05, and power of 0.80.
Analysis: The statistical analysis will be done in collaboration with Jill Barker, Ph.D.
(Consultant). Baseline patient characteristics between the 2 groups will be compared by
unpaired Student t-tests or Chi-square analysis, as appropriate. Statistical analysis will
be performed on an intent-to-treat basis. Primary and secondary graft survivals curves will
be generated by the Kaplan-Meier method. The differences in graft survival between groups
will compared by log rank test. In addition, the association between baseline clinical
characteristics and graft survival will be analyzed by univariate and multi-variable
regression analysis using the Cox proportional hazards model. The costs of all subsequent
access-related procedures, hospitalizations, and complications will be determined using
Medicare reimbursement rates in Alabama. The total cost of access care between groups will
be compared by unpaired Student t-tests.
