From the New England Society for Vascular Surgery

Multiple preoperative and intraoperative factors

predict early fistula thrombosis in the Hemodialysis
Fistula Maturation Study
Alik Farber, MD,a Peter B. Imrey, PhD,b,c Thomas S. Huber, MD, PhD,d James M. Kaufman, MD,e,f
Larry W. Kraiss, MD,g Brett Larive, MS,b Liang Li, PhD,b,h and Harold I. Feldman, MD,i for the HFM
Study Group, Boston, Mass; Cleveland, Ohio; Gainesville, Fla; New York, NY; Salt Lake City, Utah; Houston, Tex;
and Philadelphia, Pa

Objective: Early thrombosis (ET) contributes to autogenous arteriovenous fistula (AVF) failure. We studied patients
undergoing AVF placement in the Hemodialysis Fistula Maturation Study, a prospective, observational cohort study,
using a nested case-control analysis to identify preoperative and intraoperative predictors of ET.
Methods: ET cases were compared with controls, who were matched for gender, age, diabetes, dialysis status, and surgeon
fistula volume. ET was defined as thrombosis diagnosed by physical examination or ultrasound within 18 days of AVF
creation. Conditional logistic regression models were fit to identify risk factors for ET.
Results: Thirty-two ET cases (5.3%) occurred among 602 study participants; 198 controls were matched. ET was
associated with female gender (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19-6.38; P [ .018), fistula
location (forearm vs upper arm; OR, 2.76; 95% CI, 1.05-7.23; P [ .039), feeding artery (radial vs brachial; OR,
2.64; 95% CI, 1.03-6.77; P [ .043) and arterial diameter (OR, 1.52; 95% CI, 1.02-2.26; P [ .039, per mm smaller).
The draining vein diameter was nonlinearly associated with ET, with highest risk in 2- to 3-mm veins. Surprisingly,
ET risk was lower in diabetics (OR, 0.19; 95% CI, 0.07-0.47; P [ .0004), lower with less nitroglycerin-mediated
brachial artery dilation (OR, 0.42; 95% CI, 0.20-1.92; P [ .029 for each 10% lower) and higher with lower car-
otid-femoral pulse wave velocity (OR, 1.49; 95% CI, 1.02-2.20; P [ .041, for each m/s lower). Intraoperative
protamine use was associated with a higher ET risk (OR, 3.26; 95% CI, 1.28-1; P [ .038). Surgeon’s intraoperative
perceptions were associated with ET: surgeons’ greater concern about maturation success (likely, marginal, unlikely)
was associated with higher thrombosis risk (OR, 8.09; 95% CI, 4.03-1; P < .0001, per category change), as were
absence vs presence of intraoperative thrill (OR, 21.0; 95% CI, 5.07-1; P [ .0001) and surgeons’ reported frus-
tration during surgery (OR, 6.85; 95% CI, 2.70-1; P [ .0004). Decreased extent of intraoperative thrill (proximal,
mid or distal third of the forearm or upper arm, based on AVF placement) was also associated with ET (OR, 2.91;
95% CI, 1.31-1; P [ .007, per diminished level). Oral antithrombotic medication use was not significantly associated
with ET.
Conclusions: ET was found to be associated with female gender, forearm AVF, smaller arterial size, draining vein
diameter of 2 to 3 mm, and protamine use. Paradoxically, diabetes and stiff, noncompliant feeding arteries were
associated with a lower frequency of ET. Absent or attenuated intraoperative thrill, and both surgeon frustration
and concern about successful maturation during surgery, were correlated strongly with ET. (J Vasc Surg
2016;63:163-70.)

From the Division of Vascular and Endovascular Surgery, Boston Medical
Center, Bostona; the Department of Quantitative Health Sciences,
Lerner Research Institute, Cleveland Clinic,b and Department of Med-
icine, Cleveland Clinic Lerner College of Medicine of Case Western
Reserve University,c Cleveland; the Division of Vascular Surgery, Uni-
versity of Florida College of Medicine, Gainesvilled; the VA Boston
Healthcare System, Bostone; the Division of Nephrology, VA New
York Harbor Healthcare System, and Division of Nephrology, New
York University School of Medicine, New Yorkf; the Division of
Vascular Surgery, University of Utah, Salt Lake Cityg; the Department
of Biostatistics, MD Anderson Cancer Center, Houstonh; and the Cen-
ter for Clinical Epidemiology and Biostatistics, Department of Biosta-
tistics and Epidemiology, and Renal-Electrolyte & Hypertension
Division, University of Pennsylvania Perlman School of Medicine,
Philadelphia.i
The members of the Hemodialysis Fistula Maturation Study Group
are listed at the end of the Supplementary Materials and in Dember
et al.20
The HFM Study is funded by grants U01DK066597, U01DK082179,
U01DK082189, U01DK082218, U01DK082222, U01DK082236,
and U01DK082240 from the NIDDK.
Author conflict of interest: none.
Presented at the 2014 Joint Annual Meeting of the New England Society
for Vascular Surgery and Eastern Vascular Society, Boston, Mass,
September 14, 2014.
Additional material for this article may be found online at www.jvascsurg.org.
Correspondence: Alik Farber, MD, Boston Medical Center, 88 East
Newton St, Collamore, 5th Floor, Ste 506D, Boston, MA 02118
(e-mail: alik.farber@bmc.org).
The editors and reviewers of this article have no relevant financial relationships
to disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
0741-5214
Copyright Ó 2016 by the Society for Vascular Surgery. Published by
Elsevier Inc.
http://dx.doi.org/10.1016/j.jvs.2015.07.086

163

164 Farber et al
Catheters and both autogenous and prosthetic arterio-
venous access are used in maintenance hemodialysis, with
arteriovenous fistulas (AVFs) preferred because of longer
patency, less frequent intervention to maintain patency
and lower health care costs1-3 However, AVF maturation
failure rates are high, varying from 18% to 53%.3,4 Early
thrombosis (ET),4-14 which may represent the most
aggressive form of primary access failure, has been reported
to occur in 6.3% to 19.5% of fistulas, and is associated with
preoperative patient factors, including thrombophilic factor
gene polymorphisms15 and radial artery diameter,16 intrao-
perative factors such as surgeon experience,17 end-diastolic
velocity in the proximal feeding artery after AVF construc-
tion, and absence of bruits and postoperative factors
including arterial resistive index18 and use of anticoagu-
lants,4,12 as well as intraoperative6 and postoperative10 fis-
tula blood flow.
Evaluation of risk factors for ET has been hampered, in
part, by lack of a standard definition and the reporting of
ET as a component of maturation failure rather than as a
separate outcome.19 Identifying patients at high risk for
ET could lead to better selection of candidates for AVF
creation and/or suggest more appropriate remedial
postoperative procedures. We studied participants in the
Hemodialysis Fistula Maturation (HFM) Study, a seven-
center prospective, observational cohort study of patients
with newly created AVFs, to identify preoperative and
intraoperative risk factors for ET.
METHODS
The design of the HFM Study has been described in
detail previously.20 Eligibility criteria included age younger
than 80 if not yet on maintenance dialysis, life expectancy of
greater than 9 months, current or anticipated need for main-
tenance hemodialysis within 3 months of AVF construction,
and placement of an autogenous, single-stage AVF. Infor-
mation obtained preoperatively included demographic
characteristics, comorbid illnesses, and self-reported use
of medications. Brachial artery flow-mediated dilation
(FMD) and nitroglycerin-mediated dilation (NMD), arte-
rial pulse wave velocity (PWV) measurement and venous
occlusion plethysmography were performed at baseline to
assess vascular function. Duplex ultrasound measures,
including vessel diameters, flow rates, and arterial calcifica-
tion, were used to assess vascular anatomy. Processes of
care including training and experience of the surgical
team, technique for AVF creation, intraoperative manage-
ment, dialysis practices, perioperative medications, vessel
size, anesthesia type, procedural details, and duration of
the operation were noted. The attending surgeon’s intrao-
perative assessment of AVF thrill (absent or extending to
proximal, mid, or distal third of upper arm or forearm),
expressed frustration (yes/no), and prediction of success
(likely, marginal, unlikely) were recorded. Intraoperative fis-
tula vein samples were obtained for histopathologic analysis
of hyperplasia and calcification. Postoperative serial duplex
ultrasonographies were performed within 3 days and at 2
and 6 weeks postoperatively in 94%, 92% and 88% of
JOURNAL OF VASCULAR SURGERY
January 2016
participants, respectively, and as clinically requested by the
participant’s physician (see Supplementary Methods, online
only, for ultrasound, vascular function, and histologic assess-
ments). The HFM Study was approved by the institutional
review boards of all participating institutions and all patients
provided consent to participate.
Thrombosis was diagnosed clinically during scheduled
HFM postoperative visits and also at duplex ultrasound ex-
aminations. We postulated that early thrombotic cases rep-
resented a distinct set of failure mechanisms that would
manifest themselves rapidly. We defined ET as those cases
that occurred within 18 days after fistula creation, allowing
incorporation of the 2-week ultrasound examination and af-
ter which a gap and substantial decline in frequency of ET
diagnoses was observed (Supplementary Fig, online only).
Owing to the statistical limitations of multivariable
modeling with few outcome cases per predictor, we per-
formed a nested case-control analysis. Control patients
were those without ET who could be simultaneously
matched to any ET patient (case) based on sex, age
(68 years), diabetes, whether or not on maintenance dialysis
at time of enrollment, and surgeon past experience in creating
AVFs based on the attending surgeon’s reported number
of AVF operations performed in 2007 through 2009 (just
before initiation of the HFM Study consortium, 670). These
controls were optimally partitioned into disjoint sets,
matched to each individual case21 (Appendix A, online
only). To study gender in relation to ET, adjusted for other
matching variables, we created new matched sets after
removing gender from the matching criteria, and proceeded
analogously for other matching variables.
The method of case-control matching, variables for
case-control comparisons, choices of one- or two-sided
testing and criterion for statistical significance were prede-
termined for each variable. We also designated outcome hi-
erarchies (primary, secondary, other) or prespecified
Bonferroni multiple comparison adjustments, to limit the
potential occurrence and emphasis placed on false positive
results from multiple testing of correlated variables
(Appendix B, online only).
Conditional logistic regression within the resulting
matched sets was used to estimate and test associations of
ET with candidate variables, with splines used to screen
for general nonlinear effects (Appendix A, online only).
Significant associations were reexamined after covariate
adjustment for oral antithrombotic medication defined as
the use of aspirin, clopidogrel, warfarin, or aspirin/dipyri-
damole reported at the screening visit (yes/no).
Because FMD% and NMD% may not account
adequately for variation in vessel size between individ-
uals,22 we included two allometrically adjusted alternatives
to these percentage measures, based on linear regression of
log (post-stimulus vessel diameter) on log (prestimulus
vessel diameter), as exploratory measures. These replace
each percentage measure as predictor respectively by (i)
the patient’s residual from this regression or (ii) the ratio
of post-stimulus diameter to (prestimulus diameter)b,
where b is the estimated regression coefficient.22
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1
Table I. Matching variables and maintenance antithrombotic therapy among Hemodialysis Fistula Maturation (HFM)
Study participants with early fistula thrombosis, those without ET, and controls
Participants without ET Participants with ET Weighted,a matched controls
Variable
Female, %
Age, years, mean 6 SD
Diabetes, %
On maintenance hemodialysis, %
Attending surgeon fistula surgery experience,b mean 6 SD
Maintenance antithrombotic therapy use at screening, %
ET, Early fistula thrombosis; SD, standard deviation.
a
Weighted statistics are simple averages of summaries (means or %) within the sets of controls matched to each individual ET case.
b
Fistulas (total number) created by attending surgeon in the 3 years before initiation of the HFM Study.
Joint distributions of several intraoperative variables
found to be associated strongly with ET were examined
for redundancy. To assess and illustrate the potential pre-
dictive capacity of intraoperative surgeon perceptions,
guided by bivariate associations we devised a simple ad
hoc algorithm combining two predictors, and calculated
its sensitivity and specificity (the respective fractions of ET
cases and noncases correctly anticipated by the algorithm),
and its positive and negative predictive values (the respec-
tive fractions of the algorithm’s ET and no-ET predictions
that proved to be correct) within the full HFM cohort.23
Computations were performed using SAS 9.3
PROC LOGISTIC and other components, and the
LGTPHCURV9 macro24 for spline fitting. Unless
otherwise noted, statistical significance was assessed us-
ing two-sided 5% level tests.
RESULTS
Cases and matched sets. The 602 HFM Study partic-
ipants had a mean age of 55.1 6 13.4 years with 37% being
more than 60 years old. Thirty percent of participants were
female, 44% were African American, 59% had diabetes, and
64% were on maintenance dialysis (see the Supplementary
Materials and Supplementary Table I, online only, for
additional summary information regarding this cohort and
the specific timing of all ET diagnoses through 60 days
postoperatively). Thirty-five patients developed ET within
the first 30 days after AVF creation and 32 patients (5.5%
of HFM enrollees) were diagnosed within the first 18 days
of surgery. Of these 32 patients, 9 were diagnosed by
physical examination, 2 by duplex ultrasonography, and 21
using both modalities.
Consistent with prior studies, ET was more common
among women than men (7.7% vs 4.7%), and in AVFs con-
structed from vessels 2.0 to 3.0 mm than from those
greater than 3.0 mm in diameter (arteries, 7.8 vs 4.6%;
veins, 8.5 vs 4.5%). ET occurred in 3 of 30 AVFs (10%)
constructed from less than 2.0 mm arteries but, interest-
ingly, in only 3 of 103 (2.9%) constructed from less than
2.0 mm veins, including 0 of 29 such AVFs in women
(Supplementary Table II, online only).
Farber et al 165
Subgroup
(n ¼ 570) (n ¼ 32) (n ¼ 198)
29.1 40.6 40.6
55.5 6 13.4 49.1 6 11.8 50.5 6 11.6
60.7 21.9 21.9
64.2 65.6 65.6
169.7 6 138.9 211.3 6 145.8 210.3 6 146.0
53.3 37.5 39.6
A total of 198 HFM Study participants without ET
were matched to ET cases, with the number of controls
varying from 1 to 38 per case. Table I summarizes the
five matching variables, as well as antithrombotic usage,
for cases, all noncases and the averages of controls matched
with each case. The proportions of cases and weighted pro-
portions of controls with each dichotomous matching fac-
tor were identical, by construction. Mean age was matched
within 1.4 years, mean surgeon fistula creation experience
within 1.1 surgeries, and baseline reported oral antithrom-
botic use was noted to be within 2.2%.
Baseline clinical and demographic characteristics.
Early thromboses were significantly more common in fe-
males (odds ratio [OR], 2.75; 95% confidence interval
[CI], 1.19-6.38; P ¼ .018) and seen more frequently among
African Americans than other races, although the latter effect
was not significant (OR, 1.90; 95% CI, 0.80-4.50; P ¼ .15;
Table II). Estimated ORs for age, body mass index, smok-
ing, hypercoagulability disorder, renal diagnosis, current
maintenance hemodialysis, ipsilateral catheter use, and use
of antithrombotic medications were not significant.
Of note was the low frequency of ET among partici-
pants with diabetes. Only 2% of study participants with dia-
betes experienced ET compared with 10% of those without
diabetes. The inverse association of diabetes with ET was
highly significant after matching for age, gender, dialysis
status, and surgeon fistula creation experience (OR, 0.19;
95% CI, 0.07-0.47; P ¼ .0004; Table II). The proportions
of upper arm (vs forearm) AVFs were similar for cohort
members with and without diabetes (79.6% and 73.4%,
respectively). Participants with a self-reported history of
diabetes more frequently reported antithrombotic medica-
tion use at baseline than those without diabetes (61.5% and
39.8%, respectively) and had stiffer arteries as measured by
carotid-femoral PWV (mean, 11.74 vs 9.40 m/s). Adjust-
ments for these and other potential confounders, including
fistula location, feeding artery and its diameter, only
modestly attenuated the inverse association between dia-
betes and ET (data not shown).
Baseline vascular anatomic characteristics. The
artery on which the anastomosis was based (radial vs
 JOURNAL OF VASCULAR SURGERY
166 Farber et al January 2016

Table II. Association of baseline clinical and Table III. Association of baseline vascular anatomical
demographic characteristics with early fistula thrombosisa characteristics with early fistula thrombosisa

P Risk factor No.b OR 95% CI P value

Risk factor No.b OR 95% CI value
Fistula configuration variables
Demographic factors Forearm vs upper arm 225 2.76 1.05-7.23 .039
Female vs malec 327 2.75 1.19-6.38 .018 Radial vs brachial 225 2.64 1.03-6.77 .043
Age (per decaded) 445 0.86 0.65-1.14 .28 Basilic vs cephalic 225 1.27 0.47-3.44 .64
African American vs 222 1.90 0.80-4.50 .15 Most common configurations 225 d d .077
other races Forearm cephalic vs upper d 3.38 1.17-9.77 d
Other nonclinical factors arm cephalic
BMI >30 kg/m2 230 1.19 0.53-2.70 .67 Upper arm basilic vs upper d 1.89 0.61-5.82 d
Ever smoker 228 0.70 0.31-1.57 .39 arm cephalic
Pack-years, among 71 1.01 0.99-1.03 .41 Upper arm basilic vs forearm d 0.59 0.17-1.85 d
ever-smokers cephalic
Years since last smoked 49 1.08 0.96-1.22 .20 Feeding artery diameter 222 1.52 1.02-2.26 .039
among former smokers (per 1 mm thinner)
(per decreasing decade) Feeding artery cross-sectional 222 1.98 0.97-4.04 .060
Preoperative diagnoses area (per 1 mm2 reduction)
Diabetese 360 0.19 0.07-0.47 .0004 Minimum draining vein 225 d d c

Known hypercoagulable 230 0.71 0.14-3.58 .68 diameter (per 1 mm

state thinner)
Kidney disease diagnosis 102 d d .82 Minimum draining vein 225 2.03 0.86-4.77 .10
Glomerulonephritis d 1.45 0.14-15.3 d cross-sectional area (per
vs pooled 1 mm2 reduction)
diabetic nephropathy/ Preoperative vascular pathology
ischemic renal disease measures
Hypertensive d 0.98 0.10-9.43 d Feeding artery ultrasound 224 1.34 0.63-2.86 .44
nephrosclerosis vs calcification index
pooled diabetic (per severity level)
nephropathy/ Draining vein histologic 203 1.17 0.24-5.78 .85
ischemic renal disease calcification (intimal and/
Glomerulonephritis vs d 1.49 0.42-5.26 d or medial vs none)
hypertensive Draining vein histologic 101 1.19 0.94-1.50 .15
nephrosclerosis neointimal hyperplasia
Current therapies index (per 10% increase)
Chronic (maintenance) 331 1.15 0.46-2.89 .77
dialysisf CI, Confidence interval; HFM, Hemodialysis Fistula Maturation; OR, odds
Ipsilateral catheter use 155 0.99 0.11-8.55 .99 ratio.
a
No antithrombotic 230 1.23 0.52-2.93 .63 Unless otherwise noted, case-control comparisons are matched on baseline
medicationg sex, age, diabetes, chronic dialysis, and surgeon’s fistula creation surgeries
(during 2007-2009, preceding HFM Consortium), and hypothesis tests are
BMI, Body mass index; CI, confidence interval; HFM, Hemodialysis Fistula two-tailed with P # .05 required for statistical significance.
b
Maturation; OR, odds ratio. Number of patients in matched sets that are statistically informative, in the
a
Unless otherwise noted, case-control comparisons are matched on baseline sense that data on the risk factor was present for both at least one case and
sex, age, diabetes, chronic dialysis, and surgeon’s fistula creation surgeries one matched control.
(during 2007-2009, preceding HFM Consortium), and hypothesis tests are c
Varies with diameter: model P ¼ .036, nonlinearity P ¼ .035, with a
two-tailed with P # .05 required for statistical significance. highest-risk plateau from roughly 2.0-3.0 mm.
b
Number of patients in matched sets that are statistically informative, in the
sense that data on the risk factor was present for both at least one case and
one matched control. draining vein diameter nonlinearly related [P ¼ .036],
c
Matched on baseline age, diabetes, chronic dialysis, and surgeon’s fistula with highest risk over a plateau for 2- to 3-mm diameter
creation surgeries (during 2007-2009, preceding HFM Consortium).
veins; Table III). Fistulas located in the forearm had an
d
Matched on baseline sex, diabetes, chronic dialysis, and surgeon’s fistula
creation surgeries (during 2007-2009, preceding HFM Consortium). higher odds of ET than those placed in the upper arm (OR,
e
Matched on baseline age, sex, chronic dialysis, and surgeon’s fistula crea- 2.8; 95% CI, 1.05-7.2; P ¼ .039). An overall test of dif-
tion surgeries (during 2007-2009, preceding HFM Consortium). ferences among the three most common configurations
f
Matched on baseline age, sex, diabetes, and surgeon’s fistula creation sur- (forearm cephalic, upper arm basilic, upper arm cephalic)
geries (during 2007-2009, preceding HFM Consortium).
g
No current use of aspirin, clopidogrel, warfarin, or aspirin/dipyridamole
approached but did not attain significance (P ¼ .08),
reported at screening visit. although forearm cephalic AVF had higher ET odds than
upper arm cephalic AVF in direct pairwise comparison
(OR, 3.38; 95% CI, 1.2-9.8). Feeding artery and draining
brachial), and feeding artery and draining vein diameters, vein calcification, vein neointimal hyperplasia, and cross-
prespecified as primary anatomical variables, were each sectional areas were not associated with ET.
associated significantly with ET (radial vs brachial: OR, Baseline vascular function. ET was associated with
2.6 [95% CI, 1.0-6.8; P ¼ .043]; feeding artery diameter: greater brachial artery NMD (OR per 10% increase in
OR, 1.5 [95% CI, 1.0-2.3; P ¼ .039] per mm narrower; NMD%, a primary variable, 2.36; 95% CI, 1.09-5.10;
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1
Table IV. Associations of preoperative measures of
vascular function with early fistula thrombosisa
Risk factor No.b OR 95% CI P value
Brachial artery dilation measures
FMD% (per 10% decline) 198 0.51 0.21-1.22 .13
NMD% (per 10% decline) 140 0.42 0.20-0.92 .029
Arterial stiffness measures
Carotid-radial PWV 101 1.06 0.79-1.43 .68
(per m/sec decline)
Carotid-femoral PWV 101 1.49 1.02-2.20 .041
(per m/sec decline)
Fistula forearm vein
function measures
Capacitance slope 217 1.14 0.94-1.38 .19
(per 0.1%/10 mm Hg
pressure decline)
Maximum vein output slope 217 1.21 0.96-1.51 .10
(mL/100 mL/min)/
(10 mm Hg pressure decline)
CI, Confidence interval; FMD, flow-mediated dilation; NMD, nitrogen-
mediated dilation; OR, odds ratio; PWV, pulse wave velocity.
a
Unless otherwise noted, case-control comparisons are matched on baseline
sex, age, diabetes, chronic dialysis, and surgeon’s fistula creation surgeries
(during 2007-2009, preceding Hemodialysis Fistula Maturation Con-
sortium), and hypothesis tests are two-tailed with P # .05 required for
statistical significance.
b
Number of patients in matched sets that are statistically informative, in the
sense that data on the risk factor was present for both at least one case and
one matched control.
P ¼ .029), and with less trunk artery stiffness as assessed by
PWV (OR per 1 m/s decline in carotid-femoral PWV, a
secondary variable, 1.49; 95% CI, 1.20-2.20; P ¼ .041)
but not with carotid-radial PWV, a primary variable (OR,
1.06; 95% CI, 0.79-1.43). The OR for FMD% was
similar in magnitude to that for NMD%, but did not
attain significance (Table IV). Allometric alternatives to
FMD% and NMD% yielded similar results with slightly
greater variability and P values. The association of ET with
NMD was attenuated after allometric adjustment (P ¼
.062; data not shown). The remaining measures of vascular
function were not associated with ET.
Surgeon and surgical factors. No associations of ET
with subspecialty training of the attending surgeon or
whether the attending or a trainee performed the anasto-
mosis were found (Table V). The following factors were
associated significantly with increased risk for ET: Prot-
amine use to reverse heparin-induced anticoagulation (OR,
3.26; 95% CI, 1.28-1; P ¼ .038); surgeon’s perception of
thrill (OR, 21.0 [95% CI, 5.07-1; P ¼ .0001] for absence
vs presence of thrill; OR, 2.91 [95% CI, 1.31-1; P ¼ .007]
for decreased extent of thrill, when present [proximal vs
mid or mid vs distal third of either the forearm or upper
arm, depending on AVF placement]), and surgeon’s pre-
diction of fistula outcome (OR, 8.09 [95% CI, 4.03-1,
P < .0001] for each successive worse level [likely, marginal,
unlikely] of prognostic concern). Surgeon-reported frus-
tration at the end of surgery was also strongly associated
with ET (OR, 6.85; 95% CI, 2.70-1; P ¼ .0004). A
common correlate of diminished thrill, prognostic concern,
Farber et al 167
and surgeon frustration was duration of the operative
procedure, which in the full cohort was longer by
approximately 0.75 hours when the surgeon was frustrated
or when success was viewed as unlikely vs likely, and by
0.46 hours for surgeries without perceptible thrill at clos-
ing. A composite of the surgeon’s belief that success was
unlikely or marginal combined with the surgeon’s
expressed frustration predicted ET with 44% sensitivity,
97% specificity, 54% positive predictive value, and 97%
negative predictive value. Thus, roughly one-half of such
fistulas (54%) thrombosed early. Absent or attenuated thrill
on surgical closing was a related and a less subjective
negative prognostic sign. Estimated ORs for regional or
local vs general anesthesia, postoperative ball-squeezing
recommendation, or use of topical vasodilator, thrombin,
or vessel loops, were not significant. Desmopressin was not
tested owing to very infrequent use.
Antithrombotic use. Self-reported antithrombotic
use ascertained at screening exhibited no clear association
with ET. Results for other variables were not changed
materially by further adjustment for antithrombotic usage.
DISCUSSION
ET (within 18 days of surgery) occurred in 5.5% of pa-
tients in the HFM Study, an unusually large and compre-
hensive prospective, multicenter, observational cohort
study of men and women with newly created AVFs. We
examined the Dialysis Access Consortium (DAC) Study
database, and found that a virtually identical 6.0% of pa-
tients experienced ET within 18 days (retrieved from
DAC Study database by M. Radeva, DAC Study DCC,
personal communication, April 14, 2014). ET may repre-
sent the worst functional outcome on the AVF maturation
spectrum. Identifying ET predictors could facilitate recog-
nition of patients for whom placing an alternative dialysis
access may be preferable to creating an AVF.
ET risk was higher in women than in men, for forearm
than upper arm fistulas, for radial than brachial artery fis-
tulas, and for fistulas constructed from smaller caliber
arteries or veins, although the trend for veins surprisingly
did not extend below vessels 3 mm in diameter. ET risk
was unexpectedly much lower in diabetic than in nondia-
betic patients, and unexpectedly higher in patients with
better brachial artery NMD or more compliant central ar-
teries. Absent or attenuated intraoperative thrill and sur-
geon frustration and concern about the fistula’s prospects
at the close of surgery were strongly associated with ET.
Studies support the predictive value of surgeon imme-
diate postoperative risk assessments and frustration during
surgery in predicting complications of thyroid, abdominal,
and hernia surgeries,24-26 although intraoperative surgeon
opinion on the success of endoscopic repair of vesicoure-
teral reflux only poorly predicted cure.27 Associations of
surgeon factors with AVF thrombosis have not been well-
studied. In the United States, dialysis access surgery is per-
formed by general, vascular, transplant, and cardiothoracic
surgeons, who may or may not be board certified in their
respective fields. Our findings support our hypothesis that
 JOURNAL OF VASCULAR SURGERY
168 Farber et al January 2016

Table V. Associations of surgeon and intraoperative variables with early fistula thrombosisa

Risk factor No.b OR 95% CI P value

Surgeon factors
Recommends postoperative ball 230 0.41 0.16-1.01 .053
squeezing less often (per
category: always or almost
always, sometimes, never)
CT subspecialty certificationc No CT-certified HFM surgeons
Transplant subspecialty 230 2.55 0.68-9.50 .16
certificationc
Vascular subspecialty certificationc 230 0.35 0.12-1.04 .06
Surgical subspecialty certificationc 230 0.41 0.09-1.78 .16
Vascular access surgeries in 3 417 0.98 0.95-1.01 .15
pre-HFM years (per 10 fewer
surgeriesd)
Intraoperative factors
Local or regional anesthesia 230 2.09 0.82-5.38 .13
Arteriotomy length (per mm 112 0.72 0.51-1.03 .071
shorter)
Topical thrombine 230 1.06 0.38-1 .23
Heparine,f 230 0.88 0-1.07 .15
Fixed (vs weight-based) heparin 98 1.68 0.72-3.93 .23
dosef
Protaminee,f 98 3.26 1.28-1 .038
Desmopressine Virtually unused, hence not tested
Anastomosis by fellow or resident 230 0.42 0.11-1.58 .20
Topical vasodilator 230 1.96 0.59-6.49 .27
Vessel loops 230 0.99 0.35-2.81 .99
Surgeon assessments of fistula
No thrille 228 21.0 5.07-1 .0001
If thrill, reduced extent (per 1/3 146 2.91 1.31-1 .007
forearm/upper arme)
Predicted success (per <category: 228 8.09 4.03-1 <.0001
likely, marginal, unlikelye)
Surgeon frustratede 217 6.85 2.70-1 .0004

CT, Cardiothoracic; CI, confidence interval; HFM, Hemodialysis Fistula Maturation; OR, odds ratio.
a
Unless otherwise noted, case-control comparisons are matched on baseline sex, age, diabetes, chronic dialysis, and surgeon’s fistula creation surgeries (during
2007-2009, preceding HFM Consortium), and hypothesis tests are two-tailed with P # .05 required for statistical significance.
b
Number of patients in matched sets that are statistically informative, in the sense that data on the risk factor was present for both at least one case and one
matched control.
c
Prespecified test criterion P # .0125 for multiple comparison control.
d
Matched on baseline sex, age, diabetes, and chronic dialysis.
e
One-tailed testing with significance criterion P # .05.
f
Protamine use and type of heparin dosing (fixed or weight-based) did not show a statistically significant interaction (P ¼ .80).

these surgeons can intraoperatively anticipate the prospects
for ET of a newly constructed AVF. However, because our
predictive algorithm is ad hoc and estimates of its sensitivity
and positive predictive value are imprecise and vulnerable
to over-optimism bias, its use in practice would be inappro-
priate without first observing and confirming its value in
another large series of new AVFs.
ET odds almost tripled in women. Others have also
found female sex to be associated with maturation fail-
ure.28 Diabetes was strongly inversely associated with
ET, even after adjustment for potential confounders.
This is at odds with prior studies, which have shown
that diabetes has been directly associated with primary fis-
tula failure11 and patency loss within 6 months of use.29
However, it is roughly consistent with the less pro-
nounced DAC Study results, where 4.6% of diabetics
(19/416) and 7.3% of nondiabetics (33/450) developed
ET (retrieved from DAC Study database by M. Radeva,
DAC Study DCC, personal communication, September
3, 2014). Only a small minority of primary maturation
failures are owing to ET. In studies of maturation failure
by any cause, an inverse association of diabetes with ET
may be concealed by direct associations of diabetes with
later failure mechanisms, including perhaps later throm-
boses by other mechanisms than give rise to ET.
Vascular function tests may contribute to cardiovascular
risk prediction in uremic and related populations.30-33 ET
was associated with higher brachial artery NMD and lower
carotid-femoral PWV, both counterintuitive findings because
ET was hypothesized to be associated with impaired arterial
dilation (lesser NMD) and increased arterial stiffness (greater
PWV). Arterial function is diminished in diabetes, suggesting
the unanticipated findings for diabetes and arterial function
could be owing to confounding among these variables, but
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1
confounding by diabetes was reduced by matching on dia-
betes status, and the diabetes finding was attenuated only
modestly by adjustments for other variables.
Forearm AVF experienced ET more often than upper
arm fistulas, as did radial artery-based compared with
brachial artery-based fistulas. Others have reported higher
risks of forearm than upper arm AVFs for primary fail-
ure11,29 and failure to mature.28 Feeding artery diameter
was correlated inversely with ET. Preoperative arterial di-
ameters of radiocephalic AVF has been found to be associ-
ated inversely with immediate postoperative thrombosis16
and thrombosis up to 1 week after surgery.6 Finally, drain-
ing vein diameter was nonlinearly associated with ET. Low
fistula vein diameter has been associated with ET6 and non-
maturation.34 Although we observed a decreased incidence
of ET incidence with increasing vein diameter of greater
than 3 mm, ET were also relatively less common in veins
less than 2 mm wide.
Systemic heparin for anticoagulation was associated
with a modestly but not significantly lower ET risk, but
risk was higher when protamine was used to reverse hepa-
rin’s effect than when heparin was used alone. Protamine
is commonly used in vascular surgery,35 including dialysis
access,36 to reverse the effect of heparin. Despite its use, clin-
ical thrombosis is relatively rare, having been described after
deployment of drug-eluting stents.37 Notwithstanding,
protamine has been described to diminish significantly the
risk of bleeding complications without increasing the risk
of clinical thrombosis in carotid artery procedures.38,39
The many potential risk factors and relatively few ETs
precluded development of a statistically reliable compre-
hensive prediction model using all risk factors as covariates.
For simplicity, parsimony, and face validity in confounder
control, we took a nested case-control perspective, match-
ing controls with cases for age, gender, diabetes, prior dial-
ysis, and surgeon experience. Maintenance antithrombotic
therapy was not matched explicitly, but was well balanced
between cases and controls. This is important, because an-
tiplatelet agents have been demonstrated to decrease the
incidence of AVF thrombosis,40 although this increase
was associated with a randomized prescribed clopidogrel
intervention and our HFM results pertain to self-reported
usage at screening.
This study has several important positive features.
Cases and controls were nested in a large vascular access
cohort from seven geographically dispersed centers. Cases
were restricted specifically to the early maturation period.
We studied a large number of potential risk factors, ob-
tained under standardized protocols. Details of statistical
analysis followed a formal analysis plan, precluding ex
post facto searches for statistical significance.
However, we focused on the specific, uncommon
problem of ET because we hypothesized that ET might
occur through mechanisms distinct from those of later
thrombosis and other causes of maturation failure. Thus,
results here do not apply to later thromboses or maturation
failure generally. Owing to this specific focus, ET frequency
was low despite a relatively large AVF sample size,
Farber et al 169
permitting consideration of only a modest number of po-
tential predictors simultaneously. Measurement of NMD
and PWV could not be obtained for substantial fractions
of participants. Most important, associations from such
observational studies are vulnerable to unanticipated con-
founders, and hence can suggest but not imply causality.
CONCLUSIONS
We found ET to be associated with female sex and,
unexpectedly, relatively less common among persons with
diabetes as well as those whose arteries were stiffer and less
able to dilate. Risk was greater when protamine was used
to reverse heparin-induced anticoagulation. The surgeon’s
intraoperative assessment of thrill, expressed frustration,
and fistula prognosis were each strongly associated with ET.
AUTHOR CONTRIBUTIONS
Conception and design: AF, PI, TH, JK, LK, BL, HF
Analysis and interpretation: PI, TH, JK, LK, BL, HF
Data collection: PI, BL, LL
Writing the article: AF, PI
Critical revision of the article: AF, PI, TH, JK, LK, BL, HF
Final approval of the article: AF, PI, TH, JK, LK
Statistical analysis: PI, BL
Obtained funding: AF, PI, TH, JK, LK, BL
Overall responsibility: AF
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15. Gungor Y, Kayatas M, Yildiz G, Ozdemir O, Candan F. The presence
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19. Ernandez T, Saudan P, Berney T, Merminod T, Bednarkiewicz M,
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22. Atkinson G, Batterham AM. The percentage flow-mediated dilation
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28. Peterson WJ, Barker J, Allon M. Disparities in fistula maturation persist
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30. Taal MW. Arterial stiffness in chronic kidney disease: an update. Curr
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31. Chirinos JA, Khan A, Bansal N, Dries DL, Feldman HI, Ford V, et al.
Arterial stiffness, central pressures, and incident hospitalized heart
failure in the chronic renal insufficiency cohort study. Circ Heart Fail
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32. Lee MJ, Han SH, Lee JE, Choi HY, Yoon CY, Kim EJ, et al. Endo-
thelial dysfunction is associated with major adverse cardiovascular
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33. Karras A, Haymann JP, Bozec E, Metzger M, Jacquot C, Maruani G,
et al. Large artery stiffening and remodeling are independently associ-
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34. Lauvao LS, Ihnat DM, Goshima KR, Chavez L, Gruessner AC,
Mills JL Sr. Vein diameter is the major predictor of fistula maturation.
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35. Wakefield TW, Lindblad B, Stanley TJ, Nichol BJ, Stanley JC,
Bergqvist D, et al. Heparin and protamine use in peripheral vascular
surgery: a comparison between surgeons of the Society for Vascular
Surgery and the European Society for Vascular Surgery. Eur J Vasc
Surg 1994;8:193-8.
36. Kim YG. Anticoagulation during haemodialysis in patients at high-risk
of bleeding. Nephrology 2003;8(Suppl):S23-7.
37. Cosgrave J, Qasim A, Latib A, Aranzulla TC, Colombo A. Protamine
usage following implantation of drug-eluting stents: a word of caution.
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Likosky DS, et al. Protamine reduces bleeding complications associated
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39. McDonald JS, Kallmes DF, Lanzino G, Cloft HJ. Protamine does not
increase risk of stroke in patients with elective carotid stenting. Stroke
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40. Lok CE, Moist L. More than reducing early fistula thrombosis is
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Submitted Apr 13, 2015; accepted Jul 23, 2015.
Additional material for this article may be found online
at www.jvascsurg.org.
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1 Farber et al 170.e1

Supplementary Fig (online only). Timing of the Hemodialysis Fistula Maturation (HFM) Study thrombosis
diagnoses through 60 days after fistula creation surgery.
 JOURNAL OF VASCULAR SURGERY
170.e2 Farber et al January 2016

Supplementary Table I (online only). Baseline Supplementary Table I (online only). Continued.
characteristics of the Hemodialysis Fistula Maturation
(HFM) Study cohort (N ¼ 602) % or
Characteristic No. mean 6 SD
% or
Characteristic No. mean 6 SD Carotid artery angioplasty 5 0.8
Carotid artery endarterectomy 4 0.7
Claudication 44 7.3
Demographics
Congestive heart failure 165 27.4
Clinical site
Boston University 108 17.9 Coronary artery angioplasty 99 16.5
University of Alabama/Birmingham 41 6.8 or bypass surgery
University of Cincinnati 60 10.0 Lower extremity angioplasty 16 2.7
or bypass surgery
University of Florida 150 24.9
Myocardial infarction 77 12.8
University of Texas Southwestern 103 17.1
Stroke or transient ischemic 84 14.0
University of Utah 99 16.4
attack
University of Washington 41 6.8
Female/male 179/423 29.7/70.3 BMI kg/m2 602 30.4 6 7.6
Age (years) at fistula creation 602 55.2 6 13.4 Blood pressure at vascular
function testing, mm Hg
18-39 85 14.1
Systolic
40-49 96 15.9
Systolic BP before FMD 558 151.2 6 23.5
50-59 196 32.6
Systolic BP before NMD 458 152.7 6 22.5
60-69 150 24.9
70-88 75 12.5 Systolic BP before PWV 449 150.9 6 23.1
Race (NIH categories, self-reported) Systolic BP before venous 569 151.3 6 23.4
Native American, Aboriginal 13 2.2 plethysmography
Diastolic
Canadian or Alaskan Native,
Diastolic BP before FMD 558 84.9 6 14.5
First Nation, Aboriginal
Diastolic BP before NMD 458 85.1 6 14.2
Australian
Diastolic BP before PWV 449 84.6 6 14.3
Asian 13 2.2
Native Hawaiian or other 12 2.0 Diastolic BP before venous 569 84.8 6 14.3
Pacific Islander plethysmography
Cigarette smoking status
Black, African American, African 264 43.9
Never 272 45.2
White/Caucasian 283 47.0
Former 220 36.5
Multiracial 9 1.5
Current smoker 105 17.4
Unknown or not reported 8 1.3
Hispanic or Latino ethnicity 79 13.1 Unknown 5 0.8
(self-reported) Smoked within 5 hours before 39 7.2
completed FMD test
Highest formal education
Baseline serum biochemistry
Without high school diploma 161 26.7
Albumin, g/dL 602 3.6 6 0.6
High school graduate 163 27.1
Calcium, mg/dL 602 8.9 6 0.9
Vocational, technical, or 34 5.6
Phosphorus, mg/dL 601 5.1 6 1.5
business degree
Some college, without degree 121 20.1 Brachial artery dilation
Associate’s degree 29 4.8 Resting velocity, cm/s 554 12.8 6 5.8
Hyperemic velocity, cm/s 535 82.8 6 33.3
Bachelor’s degree 48 8.0
Baseline diameter, mm 559 4.5 6 0.8
Master’s/doctoral/professional 28 4.7
FMD% 549 4.8 6 5.0
school
Hyperemic velocity-adjusted 525 0.07 6 0.11
Unknown 18 3.0
Baseline work status FMD, %/cm/s
Not employed NMD% 460 7.2 6 6.3
Arterial pulse-wave velocity
Homemaker or student 13 2.2
Carotid-femoral velocity, m/s 448 10.7 6 3.2
Retired 127 21.1
Carotid-radial velocity, m/s 449 8.8 6 1.7
Disabled 340 56.5
Central pulse pressure, mm Hg 449 53.3 6 19.2
Not disabled 44 7.3
Augmentation index, % 449 26.0 6 13.1
Employed
Part time 31 5.2 Venous plethysmography
Full time 44 7.3 Capacitance slope, %/10 mm Hg 569 0.5 6 0.4
Maximum vein output slope, 569 3.9 6 2.9
Unknown 3 0.5
(mL/100 mL/min)/(10 mm
Medical and lifestyle
Hg pressure decline)
Diabetes history 353 58.6
On maintenance dialysis at 387 64.3 BMI, Body mass index; BP, blood pressure; FMD, flow-mediated dilation;
fistula creation NIH, National Institutes of Health; NMD, nitrogen-mediated dilation;
Cardiovascular disease history PWV, pulse wave velocity; SD, standard deviation.
Angina 89 14.8
Cardiac arrhythmias or 85 14.1
conduction problems
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1 Farber et al 170.e3

Supplementary Table II (online only). Frequency of early (#18 days postoperatively) fistula thrombosis among 602
Hemodialysis Fistula Maturation (HFM) Study patients, jointly by sex and diameters of the feeding artery and draining
vein (early thromboses/total, %, 95% Clopper-Pearson CI)a

Female Male Overall

Draining vein diameter (minimum, mm)

Feeding artery <2.0 2.0-3.0 >3.0 <2.0 2.0-3.0 3.0 Overall

diameter, mm
<2.0 0/1 2/5 0/0 0/10 0/7 1/7 3/30
0.0 (0.0-97.5) 40.0 (5.3-85.3) (0.00-30.9) (0.00-41.0) 14.3 (0.4-57.9) 10.0 (2.1-26.5)
2.0-3.0 0/9 1/18 2/11 1/23 6/41 0/26 10/128
0.0 (0.0-33.6) 5.6 (0.1-27.3) 18.2 (2.3-51.8) 4.3 (0.1-22.0) 14.6 (5.6-29.2) 0.0 (0.0-13.2) 7.8 (3.8-13.9)
>3.0 0/19 4/42 4/65 2/41 4/88 5/159 19/414
0.0 (0.0-17.7) 9.5 (2.7-22.6) 6.2 (1.7-15.0) 4.9 (0.6-16.5) 4.6 (1.3-11.2) 3.1 (1.0-7.2) 4.6 (2.8-7.1)
Overall 0/29 7/65 6/76 3/74 10/136 6/192 32/572
0.0 (0.0-12.0) 10.8 (4.4-20.9) 7. 9 (3.0-16.4) 4.1 (0.8-11.4) 7.4 (3.6-13.1) 3.1 (1.2-6.7) 5.6 (3.9-7.8)
Overall, by sex 13/170 19/402
7.7 (4.1-12.7) 4.7 (2.9-7.3)

CI, Confidence interval.

a
Thirty patients for whom artery and/or vein diameter were not available from the preoperative ultrasound examination have been omitted from this table.

170.e4 Farber et al
APPENDIX A (online only).
Details of matching and statistical analysis
Details of statistical analysis followed a formal analysis
plan. The set of all non-ET cases matched to any case within
the prescribed tolerances was optimally partitioned into
disjoint subsets matched to each individual case by optimal
full matching,21 which (i) enforced matching of sex, diabetes,
and dialysis status, and (ii) under this constraint, chose the
partition minimizing the sum of the following weighted index
of case-control age and surgeon experience disparities:
2  jcase age  control agej/(age tolerance) þ 1 
(jcase surgeon’s prior arteriovenous fistulas [AVFs] 
control’s surgeon’s prior AVFsj)/(prior AVF tolerance) ¼
jcase age  control agej/4 þ jcase surgeon’s prior
AVFs  control’s surgeon’s prior AVFsj/70,
Optimizations were performed by the R package
optmatch.41
Relationships of ET to continuous predictors were
initially examined for nonlinearity using natural cubic
splines with internal knots at the first and third quartiles,
and boundary knots at the observed extrema of the predic-
tor, by comparing the fitted spline and linear logistic
regression models based on the same predictor. If signifi-
cant nonlinearity was found by this 2 degrees of freedom
(df) comparison, then significance of the predictor’s associ-
ation with ET was based on the 3 df test of the full spline
model; otherwise, the single df linear regression Wald test
was used. For ordinal predictors, we compared the model
using category indicator variables to the pseudolinear
model based on equally spaced category scores, and based
a final test on the latter or a categorical model, depending
on whether significant nonlinearity in the equally spaced
scores was found.
APPENDIX B (online only).
Prespecified candidate predictors (unless otherwise
noted, hypothesis tests were two-tailed with P # .05
required for statistical significance)
Baseline variables
Demographic. Secondary: Age, sex, self-identified Af-
rican American vs other race.
Comorbidities. Secondary: Diabetes, obesity (body
mass index > 30 kg/m2), hypercoagulable state (added
during journal review), renal diagnosis (comparisons of
glomerulonephritis with pooled nephropathy/ischemic
renal disease; hypertensive nephrosclerosis to pooled dia-
betic nephropathy/ischemic renal disease; glomerulone-
phritis to hypertensive nephrosclerosis), chronic dialysis.
Vascular anatomy. Primary: Radial vs brachial feeding
artery, feeding artery diameter, draining vein diameter.
Secondary: Fistula location (all forearm vs all upper
arm), basilic vs cephalic draining vein, fistula configuration
(3 categories: upper arm basilic, upper arm cephalic, fore-
arm cephalic).
Exploratory: Draining vein cross-sectional area, forearm
vs upper arm among cephalic fistulas, basilic vs cephalic
JOURNAL OF VASCULAR SURGERY
January 2016
among upper arm fistulas, upper arm basilic vs forearm ce-
phalic fistulas.
Vascular function and pathology. Primary: Fistula
arm brachial artery flow-mediated dilation (FMD),
expressed as FMD%, and nitrogen-mediated dilation
(NMD), expressed as NMD%. Feeding artery ultrasound
calcification index (none, mild, moderate to severe). Draining
vein neointimal hyperplasia index. Draining vein intimal and/
or medial calcification. Carotid-radial pulse-wave velocity.
Fistula forearm vein capacitance slope.
Secondary: Fistula arm carotid-femoral pulse wave ve-
locity. Fistula forearm maximum vein output slope.
Fistula-draining vein neointimal hyperplasia area index.
Exploratory: Rescaled alternatives to FMD%: log (postin-
flation to preinflation vein diameter ratio); log scale postinfla-
tion on preinflation vein diameter regression residual;
allometrically adjusted postinflation to preinflation vein
diameter ratio. Rescaled alternatives to NMD%, as described.
Therapy. Primary: Current ipsilateral catheter use.
Secondary: Antithrombotic medication, cigarette
smoking.
Secondary: Ever smoker, pack-years (among ever
smokers), years since last smoked (among former smokers).
Surgeon factors. No surgical subspecialty certifica-
tion. No cardiothoracic subspecialty certification. No trans-
plant surgery subspecialty certification. No vascular surgery
subspecialty certification. (The four tests of physician sub-
specialty certification variables were planned as two-tailed
with Bonferroni error control, with P # .05/4 ¼ .0125
required for significance. Because no surgeons with cardio-
thoracic subspecialty certification participated in the HFM
Study, this test was not done, and tests for the other three
were conducted with significance criterion P # .05/3 ¼
.0166.) Fistulas created within 3 years before HFM Study.
Frequency of recommending postoperative ball squeezing:
never, sometimes, and always or almost always.
Intraoperative variables. Primary: Arteriotomy length,
heparin use, heparin dosing (fixed or weight based) when
heparin used; protamine, when heparin used; topical
thrombin, arteriotomy length, absence of thrill, surgeon
prognosis (success likely, marginal, unlikely).
Secondary: General vs other anesthesia (unless otherwise
noted, hypothesis tests were two-tailed with P # .05 required
for statistical significance), desmopressin, topical vasodilator,
vessel loops, thrill extent, if present (in forearm or upper arm
thirds), surgeon frustration (dichotomy), anastomosis sur-
geon (fellow or resident vs attending).
Due to the clear inherent directionality, one-tailed
testing with significance criterion P # .05 was used for
testing use of heparin, protamine, thrombin, and desmo-
pressin; absence and extent of thrill; and surgeon frustration.
SUPPLEMENTARY MATERIALS (online only).
Summary of HFM Study vascular function testing
methods
Vascular function studies were performed within
45 days before arteriovenous fistula (AVF) creation by
JOURNAL OF VASCULAR SURGERY
Volume 63, Number 1
personnel trained and certified by the HFM Vascular Func-
tion Core, on the arm planned for AVF creation unless a
patent arteriovenous access was already present. Participants
refrained from exercise after midnight and fasted for at least
6 hours before the studies, which when possible were per-
formed on 1 day in the order described. Before the first
vascular function study of any day, blood pressure and heart
rate were measured after an initial 10 minutes of supine rest,
in triplicate with at least 1 minute between readings, using a
SunTech 247 device (SunTech Medical, Morrisville, NC).
Venous occlusion plethysmography. Participants
were positioned supine with arm supported and elevated
above the level of the heart. The Hokanson EC5 strain
gauge plethysmography device with NIVP3 software
was used for waveform acquisition and analysis (D.E.
Hokanson, Inc, Bellevue, Wash). A strain gauge of appro-
priate size was placed around the forearm at its greatest
diameter to measure change in forearm circumference.
An SC10D arm cuff (Hokanson, Inc) placed on the upper
arm was inflated for 3 minutes to a designated pressure and
then deflated using an automatic rapid inflator device.
Waveforms were acquired while the cuff was inflated and
for 5 seconds after deflation was initiated. The procedure
was successively performed at cuff inflations to 20, 30,
40, 50, and 60 mm Hg, with maximum venous outflow
and fractional change in forearm volume measured at
each pressure, and estimated slopes from their respective
linear regressions on cuff pressure used as measures of
venous outflow and capacitance.
Carotid-radial and carotid-femoral arterial pulse
wave velocity. Pulse wave velocities (PWV, m/s) were
measured using the SphygmoCor device (Atcor Medical,
Itasca, Ill). Carotid-radial and carotid-femoral distances
were taken as the lengths by which the distances from the
sternal notch respectively to the radial or femoral pulse
exceeded that from the sternal notch to the carotid pulse.
Pulse waveforms were recorded using applanation tonom-
etry at the carotid followed by the radial or femoral sites,
respectively. Waveform acquisition was repeated if the
standard deviation for a set of 10 waveforms was more than
10%. The QRS complex from electrocardiogram leads
served as the reference for the origin of the pulse waveform.
Brachial artery flow-mediated dilation (FMD) and
nitroglycerin-mediated dilation (NMD). After place-
ment of a Custom Hokanson 3.2500  2200 blood pressure
cuff with a quick release sphygmomanometer (Hokanson,
Inc) on the upper arm and 10 minutes of supine rest, a
high-resolution linear ultrasound probe ($7.5 mHz) was
used to obtain 2-dimensional (2D) images of the brachial
artery and pulsed wave Doppler signals. For FMD, the
cuff was then inflated to 200 mm Hg, or 50 mm Hg
above systolic blood pressure if higher, and deflated after
5 minutes. Brachial artery Doppler signals were obtained
15 seconds after deflation. 2D images gated on the
R-wave were obtained 55-65 seconds after deflation to
determine FMD. For NMD, after similar prestimulus
imaging, acquisition was repeated 3 minutes after
administration of sublingual nitroglycerin 0.4 mg.
Farber et al 170.e5
Brachial artery diameters were extracted from the 2D
images using customized software, and resting and hyper-
emic flow were determined from the Doppler signals, at
the HFM Vascular Function Core. FMD and NMD were
expressed as the postischemia and postnitroglycerin percent
increases in brachial artery diameter, respectively.
SUPPLEMENTARY MATERIALS (online only).
Summary of HFM Study assessments of fistula vein
neointimal hyperplasia and calcification
Portions of vein were surgically removed at the time of fis-
tula creation and immediately placed in 10% neutral buffered
formalin. After 24 hours of fixation, the tissue was placed in
70% ethanol for short term-storage and shipped to the Histol-
ogy Core Laboratory. Upon receipt, the tissue was processed
into paraffin following standard protocols. Four micron sec-
tions were placed onto slides and stained with Movat’s pen-
tachrome for histology and with Alizarin red S for calcium
assessment. There were a total of 554 cases accessioned.
Morphometric analysis was performed on the Movat
pentachrome stained slides, excluding cases which were
incomplete cross sections. Photographs were taken
at 40 magnification and imported into ImagePro Plus.
Calibrated measurements were done measuring the inter-
nal elastic lamina length, external elastic lamina length,
luminal area, optimal luminal area, and total vein area.
Slides stained with Alizarin red S were scored for pos-
itive calcium deposits present in neointima, media, adventi-
tial microvessels, and adventitia.
SUPPLEMENTARY MATERIALS (online only).
Summary of HFM Study preoperative ultrasound
assessments
Preoperative ultrasound mapping of the upper extrem-
ity arteries and veins was performed using a modified proto-
col.1-3 Internal diameter (ID) measurements of the artery
and veins were performed in the anteroposterior dimension
on a transverse image with a linear transducer, typically 9
Mhz or higher. Measurements included the ID of the
brachial artery 2 cm cranial to the antecubital fossa (or the
radial and ulnar arteries if a high radial artery takeoff) and
the radial artery 2 cm cranial to the wrist. All veins were eval-
uated after sequential tourniquet placement. The cephalic
and basilic veins in the upper arm were measured at the ante-
cubital fossa, mid and cranial upper arm, and cephalic vein in
the forearm measured at the wrist, mid and cranial forearm.
Postoperative arteriovenous fistula (AVF) evaluation
was performed using a modified protocol.4 The brachial ar-
tery (and radial artery if a forearm AVF) ID measurements
were obtained 2 cm cranial to the anastomosis. The AVF
draining vein ID measurements were obtained 2, 5, 10,
and 15 cm cranial to the anastomosis. Vessel patency and
presence of thrombus were assessed.
Preoperative and postoperative ultrasound studies and
a corresponding worksheet were sent to the HFM Ultra-
sound Core. Studies were assessed for adherence to

170.e6 Farber et al
protocol and accuracy of measurements using an ultra-
sound miniPACS (Imorgan, Redwood City, Calif) as
needed. Studies were read by one of 3 board certified ra-
diologists specializing in hemodialysis ultrasound, and
data electronically entered into the Data Coordinating
Center database.
Hemodialysis Fistula Maturation (HFM) Study Group
Members of the HFM Study Group are as follows:
Chair, Steering Committee, University of Pennsylva-
nia: H. Feldman; Clinical Centers, Boston University: L.
Dember (PI), A. Farber, J. Kaufman, L. Stern, P. LeSage,
C. Kivork, D. Soares, M. Malikova; University of Alabama:
M. Allon (PI), C. Young, M. Taylor, L. Woodard, K. Man-
gadi; University of Cincinnati: P. Roy-Chaudhury (PI), R.
Munda, T. Lee, R. Alloway, M. El-Khatib, T. Canaan, A.
Pflum, L. Thieken, B. Campos-Naciff; University of Flor-
ida: T. Huber (PI), S. Berceli, M. Jansen, G. McCaslin,
Y. Trahan; University of Texas Southwestern: M. Vazquez
(PI), W. Vongpatanasin, I. Davidson, C. Hwang, T. Light-
foot, C. Livingston, A. Valencia, B. Dolmatch, A. Fenves,
JOURNAL OF VASCULAR SURGERY
January 2016
N. Hawkins; University of Utah: A. Cheung (PI), L.
Kraiss, D. Kinikini, G. Treiman, D. Ihnat, M. Sarfati, I.
Lavasani, M. Maloney, L. Schlotfeldt; University of Wash-
ington: J. Himmelfarb (PI), C. Buchanan, C. Clark, C.
Crawford, J. Hamlett, J. Kundzins, L. Manahan, J. Wise;
Data Coordinating Center, Cleveland Clinic: G. Beck
(PI), J. Gassman, T. Greene, P. Imrey, L. Li, J. Alster,
M. Li, J. MacKrell, M. Radeva, B. Weiss, K. Wiggins;
Cores: Histology Core, University of Washington: C.
Alpers (PI), K. Hudkins, T. Wietecha; Ultrasound Core,
University of Alabama at Birmingham: M. Robbin (PI),
H. Umphrey, L. Alexander, C. Abts, L. Belt; Vascular
Function Core, Boston University: J. Vita (PI, deceased),
N. Hamburg (PI), M. Duess, A. Levit; Repositories:
NIDDK Biosample Repository, Fisher BioServices: H.
Higgins, S. Ke, O. Mandaci, C. Snell; NIDDK DNA Re-
pository, Fred Hutchinson Cancer Research Center: J.
Gravley, S. Behnken, R. Mortensen; External Expert Panel:
G. Chertow (Chair), A. Besarab, K. Brayman, M. Diener-
West, D. Harrison, L. Inker, T. Louis, W. McClellan, J.
Rubin; NIDDK: J. Kusek, R. Star.