Defining the Optimal Degree of Heparin Anticoagulation for Peripheral Vascular

Interventions : Insight From a Large, Regional, Multicenter Registry

Christos Kasapis, Hitinder S. Gurm, Stanley J. Chetcuti, Khan Munir, Ann Luciano, Dean
Smith, Herbert D. Aronow, Elias H. Kassab, Michael F. Knox, Mauro Moscucci, David
Share and P. Michael Grossman
Circ Cardiovasc Interv 2010;3;593-601; originally published online November 9, 2010;
DOI: 10.1161/CIRCINTERVENTIONS.110.957381
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Defining the Optimal Degree of Heparin Anticoagulation for

Peripheral Vascular Interventions
Insight From a Large, Regional, Multicenter Registry
Christos Kasapis, MD; Hitinder S. Gurm, MD, FACC; Stanley J. Chetcuti, MD, FACC;
Khan Munir, PhD, MBA; Ann Luciano, RN, ACNP-BC; Dean Smith, PhD;
Herbert D. Aronow, MD, MPH, FACC; Elias H. Kassab, MD, FACC; Michael F. Knox, MD, FACR;
Mauro Moscucci, MD, MBA, FACC; David Share, MD, MPH; P. Michael Grossman, MD, FACC
BackgroundThe optimal degree of heparin anticoagulation for peripheral vascular interventions (PVIs) has not been
defined. We sought to correlate total heparin dose and peak procedural activated clotting time (ACT) with
postprocedural outcomes in patients undergoing PVI.
Methods and ResultsWe studied 4743 patients who received heparin during PVIs in a regional, multicenter registry.
From those, 1246 had recorded peak procedural ACT with the same point-of-care device. Periprocedural and in-hospital
outcomes were compared between patients who received a total heparin dose 60 U/kg (n2161) and 60 U/kg
(n2582). Similarly, outcomes were evaluated between groups with a peak procedural ACT 250 seconds (n855)
and 250 seconds (n391). Technical and procedural success as well as intraprocedural thrombotic events did not
differ between groups. Patients with heparin dose 60 U/kg had a higher rate of postprocedural hemoglobin drop 3
g/dL (7.09% versus 5.09%, respectively, P0.004) and a higher transfusion rate compared with those with heparin dose
60 U/kg (4.92% versus 3.15%, respectively, P0.002). In multivariate analysis, independent predictors of bleeding
requiring transfusion were total heparin dose 60 U/kg, ACT 250 seconds, female sex, age 70 years, prior anemia,
prior heart failure, low creatinine clearance, hybrid vascular surgery, rest pain, and below-knee intervention. In
propensity-matched, risk-adjusted models and after hierarchical modeling, total heparin dose 60 U/kg and ACT 250
seconds remained strong predictors of post-PVI drop in hemoglobin 3 g/dL or transfusion.
ConclusionsDuring PVI, higher total heparin dose (60 U/kg) and peak ACT 250 seconds were predictors of
postprocedural transfusion. The high technical and procedural success in all groups suggests that use of weight-based
heparin dosing with a target ACT 250 seconds in PVI may minimize the bleeding risk without compromising
procedural success or increasing thromboembolic complications. (Circ Cardiovasc Interv. 2010;3:593-601.)
Key Words: peripheral vascular disease heparin blood coagulation tests peripheral interventions

nfractionated heparin (UFH) is the most commonly used

antithrombotic agent in percutaneous peripheral vascular interventions (PVIs). The availability of a rapid point of
care assay (the activated clotting time [ACT]) led to the
assumption that an optimal level of anticoagulation could be
identified in patients undergoing percutaneous coronary interventions (PCIs).1 However, the optimal heparin anticoagulation in PVI is unknown, with current recommendations
empirically based on data from the coronary literature and the
TASC II guidelines recommending heparinization to achieve
a target ACT between 200 and 250 seconds for PVI.2 Even in

the case of coronary interventions, there is a wide range of

optimal ACT levels from as low as 200 to 250 seconds to
as high as 350 to 375 seconds suggested by different
studies,3 6 whereas more contemporary data favor a downward shift to the target ACT.4 6

Clinical Perspective on p 601

Adequate dosing with UFH is essential to suppress thrombin generation associated with balloon-induced vascular injury.7 In contrast, higher doses of heparin are associated with
bleeding complications. It is well recognized that bleeding

Received April 21, 2010; accepted September 9, 2010.

From the Division of Cardiovascular Medicine (C.K., H.S.G., S.J.C., K.M., A.L., D.S., P.M.G.), University of Michigan Health System, Ann Arbor,
Mich; the Department of Cardiology (H.S.G., S.J.C., P.M.G.), Veterans Administration Health System Ann Arbor, Ann Arbor, Mich; Michigan Heart and
Vascular Institute (H.D.A.), St Joseph Mercy Hospital, Ann Arbor, Mich; Dearborn Cardiology Associates (E.H.K.), Oakwood Hospital and Medical
Center, Dearborn, Mich; the Department of Radiology (M.F.K.), Spectrum Health Hospitals, Grand Rapids, Mich; the Department of Cardiovascular
Medicine (M.M.), University of Miami, Miami, Fla; and Healthcare Quality (D.S.), Blue Cross Blue Shield of Michigan, Ann Arbor, MI.
The online-only Data Supplement is available at http://circinterventions.ahajournals.org/cgi/content/full/CIRCINTERVENTIONS.110.957381/DC1.
Correspondence to P. Michael Grossman, MD, University of Michigan Health System Cardiovascular Center, 1500 E Medical Center Dr, SPC 5869,
Ann Arbor, MI 48109-5869. E-mail pagross@umich.edu
2010 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org

DOI: 10.1161/CIRCINTERVENTIONS.110.957381

593
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594

Circ Cardiovasc Interv

December 2010

Figure 1. Rates of transfusion and drop in

hemoglobin (Hgb) 3 g/dL in different heparin dose groups. There is an increment in
the risk of bleeding and transfusion when
heparin dose exceeds 60 U/kg.

complications, especially those requiring transfusion, are an

important predictor of adverse outcome in patients with
coronary artery disease who undergo surgical or percutaneous
revascularization.8 13 The purpose of this study was to
evaluate the relationship between the degree of heparin
anticoagulation and clinical efficacy as well as bleeding risk
in patients undergoing PVI in a regional, multicenter, multidisciplinary registry. We also investigated independent risk
factors of periprocedural transfusion because knowledge of
these factors would potentially guide a more conservative
anticoagulation target or an alternative anticoagulant strategy
in the subgroups of patients with an exaggerated bleeding
hazard.

Methods
Blue Cross Blue Shield of Michigan PVI Registry
Details of the construct, data collection, and data quality assurance
for the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Peripheral Vascular Intervention Quality Improvement Initiative (BMC2 PVI), have been described previously.14 In brief, the
BMC2 PVI registry is a prospective, multicenter registry of patients
undergoing PVI at the participating hospitals (supplemental material). Endovascular carotid interventions and aortic endografts are
not included in the registry because procedural and clinical parameters differ in these patients. A data form is compiled for each
procedure. Data quality and the inclusion of consecutive procedures
are contractually required and assured by ad hoc queries, random
chart review, and a series of diagnostic routines. The data form
comprises demographic, clinical and procedural variables, baseline
and adjunctive pharmacotherapies, and in-hospital outcome data. A
list of standard definitions using the American College of Cardiology
Data Standards Committee has been used as reference.

Data Quality Control

All data undergo a 3-step validation process, including manual
review for completeness and validity, review of rejected data forms
during the import process, and review of forms that fail diagnostic
inquiries. All sites are audited twice yearly by a nurse investigator
from the coordinating center. In addition to examining cases in
which an adverse event was recorded, a random 5% sample of cases
is audited for completeness and accuracy. The compliance and
accuracy of data in the audits is 95%. Data that are found to be

inaccurate or incomplete are corrected and feedback is provided to

the responsible centers.

Study Patients and Definitions

The study cohort for this analysis consisted of 6020 patients
undergoing PVI between January 2001 and December 2007. Patients
who received periprocedural GP IIb/IIIa antagonists, thrombolytic
agents, or who were already on heparin before the procedure, were
excluded from the analysis. We also excluded patients whose values
for heparin dose or peak ACT were missing because measurement of
peak intraprocedural ACT was not standard practice in a majority of
labs during the study period. In addition, we excluded patients with
recorded ACT 200 seconds because they would not represent
clinically acceptable targets, based on the current practice supported
by the coronary literature and the TASC II guidelines, and these
patients were more likely to be rebolused with additional heparin
after the initial ACT was checked. Because of reported variability in
ACT measurements with different point-of-care assays, we restricted
our ACT analysis to those using the same ACT device (Hemochron,
ITC, Edison, NJ).15,16 Thus, 4743 cases were considered for the
heparin analysis and 1246 cases for the ACT analysis. Of those,
42.8% had femoropopliteal interventions, 21.4% had iliac interventions, 17.2% had renal interventions, 14.1% had below-knee interventions, and 4.6% had upper extremity interventions. All patients
had confirmed peripheral arterial disease, based on 1 or more of the
following: abnormal ankle-brachial index, noninvasive imaging
studies (ultrasound, computed tomographic angiography, or magnetic resonance angiography) or invasive angiography. Initial analyses were done on 4 clinically relevant categories of heparin dose
range and 3 categories of peak ACT range, respectively, suggesting
that an increment in the risk of post-PVI drop in hemoglobin 3
g/dL and/or transfusion was associated with a total heparin dose 60
U/kg and a peak ACT 250 seconds (Figures 1 and 2). Postprocedural and in-hospital outcomes were compared post hoc between
patients who received a total heparin dose 60 U/kg and 60 U/kg.
Similarly, outcomes were evaluated between groups with a peak
procedural ACT 250 and 250 seconds.
The primary end point for this study was post-PVI bleeding,
defined as a drop in postprocedural hemoglobin 3g/dL from the
preprocedural baseline value or need for transfusion. Preprocedural
and postprocedural hemoglobin was drawn within 24 hours before
and after the procedure, respectively. Other secondary end points
included technical success (defined as successful access, deployment
of the device, and 30% diameter residual stenosis assessed by
angiography after revascularization),procedural success (defined as
technical success without periprocedural complications),17 thrombo-

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Kasapis et al

Heparin Dose in Peripheral Vascular Interventions

595

Figure 2. Rates of transfusion and drop in

hemoglobin (Hgb) 3 g/dL in different
groups of ACT. An increment in the risk of
bleeding and transfusion was observed with
ACT exceeding 250 seconds.

embolic complications (defined as atherosclerotic debris or blood

clot formed during the procedure with evidence of decreased blood
flow or occlusion), and major adverse cardiac events (MACE,
defined as a composite of death, myocardial infarction, and transient
ischemic attack[TIA]/stroke). Vascular complications were defined
as a composite of retroperitoneal hematoma, pseudoaneurysm, hematoma requiring transfusion or associated with a decrease in
hemoglobin 3 g/dL, arteriovenous fistula demonstrated by arteriography or ultrasound, and acute thrombosis or need for surgical
repair of the access site.

Statistical Analysis
Statistical analysis was performed using the SAS 9.1.3 software
(SAS Institute, Cary, NC). Descriptive statistics were used to report
baseline patient characteristics. All tests used P0.05 as the critical
value of statistical significance. The 2 and Fisher exact tests were
used to analyze categorical variables. Continuous variables were
analyzed using the Student t test and Wilcoxon rank-sum tests as
needed. The associations of ACT and weight-adjusted heparin dose
with a drop in postprocedural hemoglobin 3 g/dL or bleeding
requiring transfusion were tested by using multivariate logistic
regression models to investigate independent predictors of bleeding.
The clinical characteristics included in the model were sex, age (70
years), low body mass index (BMI) (18.5 kg/m2), history of
myocardial infarction or coronary artery bypass grafting, hypertension, low creatinine clearance (60 mL/min per 1.73 m2), hyperlipidemia, diabetes, history of heart failure or TIA/stroke, hybrid
vascular surgery and rest pain, preprocedural antiplatelet therapy,
treatment with statin, ACT (250 seconds), and heparin dose (60
U/kg). We also used intervention site variables (renal, iliac, femoropopliteal, below-knee, and upper extremity), device variables
(balloon, stent, atherectomy, intravascular ultrasound, thrombolysis,
cryoballoon, and cutting balloon) and vascular access closure devices (manual or mechanical) in the multivariate regression models.
All variables were assessed using forward selection method with a
selection criterion of P0.05.
To further adjust for the nonrandomized use of heparin dose 60
U/kg and for possible selection bias, a predictive model that adjusted
for the propensity to receive heparin 60 U/kg was also developed.18 The propensity score of receiving heparin 60 U/kg was
calculated using a nonparsimonious logistic regression model. The
variables included in the model were age (70 years), sex, low BMI
(18.5 kg/m2), history of myocardial infarction, hypertension,
coronary artery bypass grafting, diabetes, history of heart failure,
TIA/stroke, low creatinine clearance (60 mL/min per 1.73m2,
hyperlipidemia, hybrid vascular surgery, rest pain, prior antiplatelet
therapy, and intervention site variables. The propensity score was

then included as an additional explanatory variable in the final

models. Furthermore, we used the Greedy matching technique using
a macro to select patients treated with heparin 60 U/kg as
counterparts to patients treated with heparin 60 U/kg.19 More
specifically, we sought to match each patient with 60 U/kg heparin
to a patient with 60 U/kg, who had a propensity score that was
identical to 5 digits. If this could not be done, we then performed a
4-, 3-, 2-, or 1-digit match. Once this threshold was exceeded, the
patient with 60 U/kg heparin was excluded. In this way, we were
able to match 1927 cases with heparin dose 60 U/kg to 1927 cases
with heparin dose 60 U/kg. Outcomes were then compared within
this propensity-matched cohort. A similar propensity-matched cohort
was developed for peak ACT values 250 (379 cases) and 250
seconds (379 cases), and outcomes were compared. We estimated the
univariate statistical significance of the effect of higher dose of
heparin and higher peak ACT, respectively, on adverse outcomes
using generalized estimating equation cluster analysis.20,21
Given the multidisciplinary origin of data, to adjust for hospitallevel and physician-level clustering, we compared hierarchical regression modeling with the conventional logistic models to determine the statistical significance of the effect of higher dose of
heparin as well as higher peak ACT values on transfusion.2224 This
was performed with a random-effects modeling technique.20,21

Results
Among a total of 4743 patients, 2161 patients received
heparin 60 U/kg and 2582 patients received 60 U/kg. Of
those, 1246 patients had peak procedural ACT recorded and
measured with the Hemochron device (Hemochron, ITC,
Edison, NJ); 855 of them had ACT 250 seconds and 391
had ACT 250 seconds. The baseline demographic and
clinical characteristics are presented in Table 1 for the heparin
dose and ACT groups, respectively. In patients receiving
higher dose of heparin (60 U/kg), there were more women,
current smokers, and higher prevalence of low BMI and low
creatinine clearance. Furthermore, in patients receiving the
lower dose of heparin (60 U/kg), there was a higher
prevalence of coronary artery disease, diabetes, hypertension,
hyperlipidemia, congestive heart failure, chronic obstructive
lung disease, and preprocedural use of antiplatelet therapy
with more than 1 agent.
Table 2 summarizes the unadjusted rate of postprocedural
or in-hospital adverse events for the heparin dose and ACT

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596

Circ Cardiovasc Interv

Table 1.

December 2010

Baseline Demographic and Clinical Characteristics in the Heparin Dose and ACT Groups
Heparin Data Set (n4743)
Heparin
60 U/kg

Characteristics
Cases, N

Heparin
60 U/kg

ACT Data Set (n1246)

P Value

ACT
250 Seconds
855

391

68.32 (11.0)

67.98 (12.4)

0.6

334 (39.1)

169 (43.2)

0.16

2161

2582

Average age, y (SD)

68.2 (11.3)

68.7 (11.2)

0.18

Female, N (%)

869 (40.2)

1158 (44.8)

0.0013

Current smoker, N (%)

Prior CAD, N (%)
Prior diabetes, N (%)

ACT
250 Seconds

P Value

580 (26.8)

804 (31.1)

0.001

234 (27.4)

101 (25.8)

0.57

1670 (77.3)

1794 (69.5)

0.0001

684 (80.0)

316 (80.8)

0.7

997 (46.1)

1063 (41.2)

0.0006

374 (43.7)

177 (45.3)

0.6

Prior HTN, N (%)

1993 (92.2)

2329 (90.2)

0.014

801 (93.7)

369 (94.4)

0.6

Prior HL, N (%)

1766 (81.7)

1991 (77.1)

0.0001

656 (76.3)

278 (71.1)

0.03

Prior CHF, N (%)

530 (24.5)

468 (18.1)

0.0001

218 (25.5)

109 (27.9)

0.3

Prior COPD, N (%)

629 (29.1)

616 (23.8)

0.0001

246 (28.8)

106 (27.1)

0.5

Prior TIA/stroke, N (%)

646 (29.9)

729 (28.2)

254 (29.7)

113 (28.9)

0.7

Low BMI,* 18.5 kg/m , N (%)

2

0.2

38 (1.8)

92 (3.6)

22 (2.6)

8 (2.1)

0.6

Low creatinine clearance,

60 mL/min, N (%)

870 (40.9)

1170 (46.7)

0.0001

376 (44.7)

173 (45.4)

0.8

Preprocedural mono-antiplatelet
therapy, N (%)

783 (36.2)

992 (38.4)

0.12

277 (32.4)

143 (36.57)

0.14

1103 (51.0)

1206 (46.7)

0.0029

531 (62.1)

222 (56.8)

0.07

Preprocedural antiplatelet
therapy,1, N (%)

0.0002

Aspirin alone

652 (30.2%)

830 (32.2%)

0.14

82 (5.4%)

56 (7.5%)

Clopidogrel alone

116 (5.4%)

141 (5.5%)

0.8

14 (0.9%)

4 (0.5%)

0.3

1019 (47.2%)

1115 (43.2%)

786 (51.9%)

354 (47.6%)

0.06

Aspirin and clopidogrel

0.006

0.047

Presenting symptoms
Asymptomatic, N (%)
Claudication, N (%)

94 (4.3)
2363 (74)

91 (3.5)
3860 (77.2)

0.1
0.001

49 (5.7)

21 (5.4)

0.8

620 (72.5)

304 (77.7)

0.05

Limb salvage, N (%)

294 (9.2)

546 (10.9)

0.01

54 (6.3)

39 (10.0)

0.02

Rest pain, N (%)

647 (20.3)

1224 (24.5)

0.0001

131 (15.3)

87 (22.2)

0.003

49 (1.5)

57 (1.1)

24 (2.8)

12 (3.1)

0.8

Renal salvage, N (%)

0.1

CAD indicates coronary artery disease; HTN, hypertension; HL, hyperlipidemia; CHF, congestive heart failure; and COPD, chronic
obstructive pulmonary disease.
*The BMI is the weight in kilograms divided by the square of height in meters. Low BMI is defined as 18.5 according to the
Centers for Disease Control and Prevention definition.
Low creatinine clearance is defined as 60 mL/min, which is equivalent to stage 3 or more chronic kidney disease according
to the National Kidney Foundation definition.
Antiplatelets: Aspirin, clopidogrel, ticlopodine, or cilostazol.

groups. Technical and procedural success was similar in all

groups. Higher weight-adjusted heparin doses were associated with significantly more bleeding complications. Patients
with heparin dose 60 U/kg had a higher rate of postprocedural hemoglobin drop 3 g/dL (7.09% versus 5.09%,
respectively, P0.004) and a higher transfusion rate compared with those with heparin dose 60 U/kg (4.92% versus
3.15%, respectively, P0.002). There was no difference in
technical and procedural success, MACE, and thromboembolic complications in both groups.
Similarly, a higher ACT was associated with more bleeding and need for transfusion. Patients with a procedural ACT
250 seconds had a higher rate of postprocedural drop in
hemoglobin 3 g/dL (9.7% versus 4.8%, respectively,
P0.0009) and a higher incidence of transfusions compared
with the group with ACT 250 seconds (5.4% versus 2.8%,
respectively, P0.02). Technical and procedural success,

MACE, and thromboembolic complications were similar in

the two ACT groups.
There were more femoropopliteal PVIs than any other
vascular bed treated (Table 3). A significantly higher number
of femoropopliteal and below-knee interventions were performed by using 60 U/kg of heparin. The majority of the
cases were performed with retrograde arterial access with
only 12.8% of cases performed with antegrade access. The
effect of higher heparin dose and ACT on higher bleeding
rates persisted even when cases with retrograde access were
analyzed separately.
Although it is difficult to objectively standardize the
complexity of the procedure in a multicenter data base, we
studied in a separate analysis the heparin dose, bleeding
complications, and procedural success stratified according to
the location of the procedurefor example, renal, iliac,
femoropopliteal, below-knee, and upper extremityas well

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Kasapis et al
Table 2.

Heparin Dose in Peripheral Vascular Interventions

597

Postprocedural and In-Hospital Adverse Events in the Heparin Dose and ACT Groups
Heparin Data Set (n4743)
Heparin
60 U/kg

Cases, n

Heparin
60 U/kg

ACT Data Set (n1246)

P Value

ACT
250 Seconds

ACT
250 Seconds

P Value

2161

2582

855

391

Mean heparin dose, U/kg SD, or mean

ACT, seconds SD

47.99.4

82.522.0

0.0001

221.314.1

28641.7

Drop in Hgb 3 g/dL, n (%)

110 (5.09)

183 (7.09)

0.004

41 (4.8)

38 (9.7)

0.0009

68 (3.15)

127 (4.92)

0.002

24 (2.8)

21 (5.4)

0.02

142 (6.57)

255 (9.88)

0.0001

54 (6.3)

44 (11.2)

0.003

Transfusion rate, n (%)

Transfusion or drop in Hgb 3 g/dL, n (%)
MACE: Death or MI or TIA/stroke, n (%)

0.0001

15 (0.69)

16 (0.62)

0.7

6 (0.7)

3 (0.8)

Embolic complications, n (%)

3 (0.14)

11 (0.43)

0.07

3 (0.3)

1 (0.3)

0.8

Thrombotic complications, n (%)

7 (0.32)

16 (0.62)

0.14

2 (0.2)

2 (0.5)

0.4

98 (3.8)

0.02*

28 (3.3)

16 (4.1)

0.5

Vascular complications, n (%)

57 (2.64

Not crossed with wire or device, n (%)

140 (6.5)

161 (6.2)

0.73

37 (4.3)

17 (4.3)

0.98

Technical success, n (%)

1869 (86.49)

2223 (86.1)

0.6

744 (87.0)

339 (86.7)

0.9

Procedural success, n (%)

1765 (81.7)

2223 (86.1)

0.7

703 (82.2)

315 (80.56)

0.4

Mean procedure duration, min SD)

69.3342.2

92.5449.65

75.148.2

86.953.0

0.0002

0.0001

Hgb indicates hemoglobin; MI, myocardial infarction.

*This difference is driven by higher rate of bleeding complications, for example, hematomas or retroperitoneal bleeding in the high-dose heparin group, whereas
other vascular complications were similar in both groups.

as the procedure durationfor example, 57 minutes, 58 to

90 minutes, and 90 minutes. Interventions to the renal
arteries had lower heparin doses and bleeding rates as well as
higher procedural success, femoropopliteal and iliac interventions had intermediate heparin doses, bleeding rates and
procedural success, and below-knee interventions had higher
heparin doses and bleeding rates as well as lower procedural
success. Similarly, longer procedure duration was intuitively
associated with use of higher heparin dose, higher bleeding
complications, and lower procedural success. The effect of
higher heparin dose on higher bleeding rates persisted even
when patients were analyzed separately in short versus long
procedure duration.
In a multivariate analysis, higher heparin dose (60 U/kg)
was found to be an independent predictor of bleeding requiring transfusion (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.11 to 2.0; P0.01) (Table 4); other independent
predictors of bleeding were female sex, age 70 years, prior
anemia, prior heart failure, hybrid vascular surgery, rest pain,
and below-knee interventions. The c-statistic for this model
Table 3.

was 0.799. A separate multivariate logistic model was developed to avoid collinearity between heparin and ACT and also
identified ACT 250 seconds as an independent predictor of
transfusion (OR, 1.9; 95% CI, 1.06 to 3.6; P0.03). For this
model, the c-statistic was 0.812. A significant interaction was
observed between heparin dose and ACT levels (OR, 1.29;
95% CI, 1.03 to 1.6; P0.001).
Manual hemostasis was achieved in 69.7% of the patients.
There was no statistical difference in the rate of bleeding
between manual hemostasis and use of vascular closure
devices. In addition, when we stratified the patients according
to sheath size, there was no significant correlation between
sheath size and increased bleeding events.
Furthermore, in a propensity-matched cohort (Table 5) in
which each patient treated with higher dose of heparin (60
U/kg) was matched to a similar patient treated with lower
heparin dose (60 U/kg), the higher total heparin dose was
associated with significantly higher rates of postprocedural
drop in hemoglobin 3 g/dL (7.01% versus 5.14%, respectively, P0.01) and transfusion (4.67% versus 3.17%, re-

Frequency of Interventions at Different Vascular Beds Stratified by Heparin Dose and ACT Levels
Heparin Data Set

ACT Data Set

n (%)

60 U/kg

60 U/kg

P Value

n (%)

250 Seconds

250 Seconds

P Value

Renal, n (%)

866 (18.3)

438 (20.27)

428 (16.58)

0.001

290 (23.3)

Iliac, n (%)

1347 (28.4)

654 (30.26)

693 (26.84)

0.009

351 (28.2)

212 (24.8)

78 (19.95)

0.06

240 (28.07)

111 (28.39)

Femoropopliteal, n (%)

2403 (50.6)

991 (45.86)

1412 (54.69)

0.0001

589 (47.3)

0.9

395 (46.2)

194 (49.6)

0.2

Below-knee, n (%)

650 (13.7)

224 (10.37)

426 (16.5)

0.0001

139 (11.1)

89 (10.41)

50 (12.79)

0.2

Upper extremity, n (%)

211 (4.45)

102 (4.72)

109 (4.22)

0.4

59 (4.7)

38 (4.44)

21 (5.37)

0.47

Other, n (%)

124 (2.6)

65 (3.01)

59 (2.29)

0.1

39 (3.1)

26 (1.72)

13 (1.75)

0.9

Below-knee indicates popliteal, peroneal, tibial, tibioperoneal trunk, or dorsalis pedis; upper extremity, radial, brachial, subclavian, or axillary; and other, celiac,
mesenteric, distal aorta, pulmonary, or dialysis fistula.

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Table 4. Independent Predictors of Transfusion and Drop in Hgb >3 g/dL Using Logistic
Regression Models
Predictors of Drop in Hgb 3 g/dL
Variable

Predictors of Transfusion

OR

95% CI

P Value

OR

95% CI

P Value

Female sex

1.98

1.52.5

0.0001

2.3

1.73.2

0.0001

Age 70 y

1.3

0.981.7

0.06

1.4

1.052.0

0.02

Prior anemia

1.3

0.91.2

0.065

3.36

2.44.7

0.0001

NS

1.74

1.22.4

0.0009

2.47

1.155.2

0.019

Prior CHF
Low creatinine clearance,
60 mL/min/1.73 m2

3.01

1.65.4

0.0002

Hybrid vascular surgery

7.6

0.0001

6.1

3.411.2

0.0001

Rest pain

2.2

1.662.9

0.0001

3.08

2.24.2

0.0001

Below-knee

3.5

1.86.2

0.0001

3.47

1.013.5

0.0007

Heparin, 60 U/kg

1.4

1.11.8

0.01

1.5

1.112.0

0.01

ACT, 250 seconds*

2.0

1.23.2

0.001

1.9

1.063.6

0.03

Interaction term for

heparin and ACT

1.3

1.061.6

0.01

1.29

1.031.6

0.001

4.413.1

Hgb indicates hemoglobin; CHF, congestive heart failure; and NS, nonsignificant.
*The ACT was tested using a separate multivariate logistic regression analysis, excluding the heparin dose, to avoid
significant collinearity between the 2 variables.
An interaction term was created for heparin and ACT and added to the multivariate models to determine
interactions between heparin dose and ACT.

spectively, P0.016). Similarly, in a propensity-matched,

risk-adjusted model for the ACT groups (250 seconds and
250 seconds), patients with a higher ACT (250 seconds)
had significantly higher rates of postprocedural drop in
hemoglobin (10.03% versus 5.8%, P0.03) and a trend
toward more transfusion (5.54% versus 2.9%, P0.07) (Table 5). Importantly, there were no differences with respect to
technical and procedural success, MACE, and thromboembolic complications in all groups. A separate propensity-score
matching analysis by adding intervention sites (renal, iliac,
femoropopliteal, below-knee, and upper extremity) to the
models demonstrated similar findings.
The heparin patient cohort (n4743) data were obtained
from 7 different hospitals involving 75 physicians, whereas
the ACT cohort (n1246) data derived from 7 hospitals
involving 59 physicians. To adjust for hospital-level and
Table 5.

physician-level variations, a hierarchical regression model

was performed to determine the relationships between
physician- and hospital-level characteristics for each of the
outcomes. The physician- and hospital-level factors did not
have any impact on the effect of higher dosage of heparin
leading to transfusion as determined by similar ORs derived
from the hierarchical (OR, 1.4; 95% CI, 1.14 to 1.82;
P0.002) and logistical (OR, 1.5; 95% CI, 1.1 to 2.0;
P0.01) models. Similarly, the effect of higher ACT remained significant in the hierarchical (OR, 2.2; 95% CI, 1.3
to 3.7; P0.0003) as well as in the logistic model (OR, 1.9;
95% CI, 1.06 to 3.6; P0.03).

Discussion
This analysis of prospectively collected individual patient
data represents the largest study correlating the degree of

Outcomes of the Propensity-Matched Cohorts Categorized by Heparin Dose and ACT Level
Heparin Data Set

Cases, N

60 U/kg

60 U/kg

1927

1927

ACT Data Set

P Value

250 Seconds

250 Seconds

379

379

P Value

Transfusion, N (%)

61 (3.17%)

90 (4.67%)

0.016

11 (2.9%)

21 (5.54%)

0.07

Drop in hemoglobin, 3 g/dL, N (%)

99 (5.14%)

135 (7.01%)

0.01

22 (5.8%)

38 (10.03%)

0.03

MACE, N (%)

15 (0.78%)

12 (0.62%)

0.5

3 (0.79%)

3 (0.79%)

2 (0.1%)

8 (0.4%)

0.06

1 (0.26%)

1 (0.26%)

Embolus, N (%)
Thrombus, N (%)
Vascular access complication, N (%)
Not crossed with wire or device, N (%)
Procedural success, N (%)

7 (0.38%)
50 (2.6%)

13 (0.67%)

0.17

1 (0.26%)

2 (0.53%)

0.5

73 (3.8%)

0.03*

12 (3.17%)

16 (4.22%)

0.4

126 (6.5%)

103 (5.3%)

0.1

11 (2.9%)

17 (4.49%)

0.2

1563 (81.1%)

1572 (81.58%)

0.7

314 (82.8%)

304 (80.2%)

0.3

Hgb indicates hemoglobin; MACE are defined as a composite of death or myocardial infarction or TIA/stroke.
*This difference is driven by higher rate of bleeding complications, for example, hematomas or retroperitoneal bleeding in the
high-dose heparin group, whereas other vascular complications were similar in both groups.

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Kasapis et al
anticoagulation with heparin and early postprocedural outcomes in PVI. The key findings of our study were that during
PVI, a higher total heparin dose (60 U/kg) and a peak
procedural ACT 250 seconds were predictors of postprocedural bleeding events. Moreover, the technical and procedural success was high and the rate of thromboembolic
complications was low and did not differ between groups.
These findings suggest that use of weight-based heparin
dosing (initially, up to 60 U/kg) with a target ACT 250
seconds may improve outcomes in PVI.
A previous single-center, retrospective study evaluated
in-hospital complications of peripheral interventions in which
UFH was the primary anticoagulant in 131 patients (with
ACT recorded in 114) and reported a nonsignificant trend
toward higher adverse events with increased weight-based
doses of heparin and no significant relationship between ACT
and adverse events, although there was a relationship between
heparin dosage and ACT level.25 The rate of major bleeding
in this study increased from 2.1% with heparin dose 30 to
54.9 U/kg to 5.4% with heparin dose 55 to 99.9 U/kg. This is
in agreement with our findings, in which patients with
heparin dose 60 U/kg had higher rates of drop in hemoglobin of 3 g/dL (7.09%) and transfusion (4.92%) compared
with those with heparin dose 60 U/kg (5.09% and 3.15%,
respectively).
Most of the data related to the optimal degree of anticoagulation with heparin for arterial percutaneous interventional procedures are extrapolated from the coronary literature. A previous meta-analysis of 6 randomized, controlled
trials of novel adjunctive antithrombotic regimens for PCI, in
which UFH constituted the control arm, demonstrated an
optimal target of ACT in the range of 350 to 375 seconds
that provided the lowest composite ischemic event rate.3
However, this degree of anticoagulation was associated with
a higher incidence of bleeding, increasing from 8.6% within
an ACT range of 325 to 350 seconds to 12.4% at ACT of 350
to 375 seconds.
Subsequent and more contemporary studies favored a
downward shift in the target ACT levels in PCI.4 6 Accordingly, a post hoc analysis of the population enrolled in the
ESPRIT trial (Enhanced Suppression of the Platelet GP
IIb/IIIa Receptor with Integrilin Therapy), comparing the use
of eptifibatide versus placebo in patients undergoing PCI with
stent, demonstrated that the incidence of ischemic events did
not increase as ACT decreased at least to a level of 200
seconds, whereas bleeding events did increase with increasing ACT levels.4 Notably, the recommended initial bolus of
heparin dose in this trial was 60 U/kg, which is the cutoff that
we used in our study. The ESPRIT investigators concluded
that an ACT level of 200 to 250 seconds is reasonable in
terms of efficacy and safety with the use of contemporary
technology and pharmacotherapy. Within the same conceptual framework, a large pooled analysis of the UFH-treated
patients enrolled in 4 recent large, randomized trials using a
median ACT of 276 seconds demonstrated that in patients
undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest linear association with bleeding
complications, suggesting that lower ACT values do not

Heparin Dose in Peripheral Vascular Interventions

599

appear to compromise efficacy while increasing safety.6

Notably, these trials assessed the concurrent use of UFH and
GPIIb/IIIa antagonists, whereas in our study the use of UFH
alone was evaluated. Therefore, even in the absence of the use
of GP IIb/IIIa antagonists, a lower ACT or heparin dose in
PVI does not result in more thromboembolic complications.
Although it appears simple to extrapolate the evidence
from coronary interventions and apply it to the peripheral
arteries, the relationship between heparin dosingACT levels
and bleeding complications, as well as procedural outcomes,
may be less evident in straightforward cases of coronary
stenting than in more prolonged and complex peripheral
arterial procedures. Therefore, the results of our analysis
provide further insight in defining the optimal degree of
heparin anticoagulation during PVI. In addition, it is well
documented that bleeding complications, especially those
requiring transfusion, remain an independent, strong predictor of adverse outcomes in patients undergoing PCI.8 11,13,26
Even though there is no current evidence on the prognostic
implications of bleeding complications in PVI, patients with
peripheral arterial disease represent an equivalent high-risk
cohort, often with significant comorbidities, such as coronary
artery disease, diabetes, and renal dysfunction. Therefore, it is
essential to minimize bleeding risk while maintaining a safe
anticoagulation level during PVI.
Although our registry analysis establishes the evidence
base for a higher safety threshold for a target ACT in PVI, the
question of a lower safe ACT threshold remains to be
answered. It is possible that lower levels of anticoagulation
may be sufficient and safe in PVI, given the large vessel size,
especially in those patients already on dual antiplatelet
therapy. Within this concept, a randomized, double-blind,
prospective study demonstrated that in the treatment of
uncomplicated coronary lesions and in the presence of dual
antiplatelet therapy with aspirin and clopidogrel, elective PCI
could be safely performed without systemic anticoagulation
and was associated with a reduced incidence of bleeding
complications.27 However, this interesting hypothesis has not
been studied yet in PVI, it cannot be answered within the
setting of a real-life registry using the current guidelinedriven standards of care, and it will require a future randomized, prospective clinical study to address this question.
Beyond the heparin dose and the ACT level, in the
multivariate analysis we found that female sex, creatinine
clearance 60 mL/min per 1.73m2 age 70 years, preprocedural anemia, history of heart failure, hybrid vascular
surgery, rest pain, and below-knee interventions were independent predictors of higher postprocedural bleeding risk.
These findings are consistent with those from 2 large retrospective databases of patients undergoing PCI13,28 and a
registry of 24 045 patients with acute coronary syndromes
from the Global Registry of Acute Coronary Events
(GRACE).29 Less aggressive anticoagulation, or use of an
alternative anticoagulant strategy such as a direct thrombin
inhibitor, may decrease the incidence of bleeding complications in these subgroups of high-risk patients.30 33

Limitations
Our findings are based on observational, prospectively collected data, and, inevitably, there were significant differences

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December 2010

in the demographic and clinical characteristics. Although we

adjusted using multivariate logistic regression and propensity
analysis, it is possible that other confounding factors may
have influenced outcomes. In addition, this database spans a
period of 7 years and encompasses a heterogeneous group of
endovascular interventions and advancing interventional
techniques as well as reflecting multiple institutions and
operators. Even though we have tried to adjust for hospitaland operator-specific clustering by using hierarchical regression techniques, operator-specific variations in procedural
outcomes as well as in heparin dosing and ACT target are also
inherent limitations of our study. However, this represents a
real-life data base, and these procedures will continue to be
performed by multiple operators from different specialties,
including interventional cardiologists, interventional radiologists, and vascular surgeons as well as in both academic and
private institutions. Because of inherent differences in the
measurement of ACT by different ACT devices15,16 and to be
consistent, we have restricted our ACT data to those measured by the Hemochron device only, which was the most
common device used in our registry. This obviously limits
our ability to generalize the findings to other devices. It
should be also noted that the study cohort for this analysis
consisted of patients undergoing PVI using the old formulation of heparin available in the United States. However,
effective as of October 2009, a new formulation of heparin is
available in the United States, and, according to the FDA
public health alert, there is an approximate 10% decrease in
the potency of the new heparin compared with the old
heparin.34 This dose adjustment should be taken into consideration when the new heparin is used. Furthermore, the
suggested weight-based heparin dosing (initially up to 60
U/kg) with a target ACT of 250 seconds, as opposed to
empirical dosing, should serve as a general guide for
heparin anticoagulation in PVI and should not substitute for
the individualization of dose in specific subgroups of patients
who are at higher bleeding risk, necessitating a more conservative dose, or, conversely, are resistant to heparin requiring
higher doses.

Conclusion
Notwithstanding these limitations, this is the first large-scale
study to evaluate the optimal degree of heparin anticoagulation in PVI. This study suggests that use of weight-based
heparin dosing (initially up to 60 U/kg) with a target ACT
250 seconds in PVI may minimize the bleeding risk without
compromising procedural success or increasing thromboembolic complications. Future prospective, randomized studies
are warranted to further validate these findings and potentially establish a lower safe ACT threshold for peripheral
vascular interventions.

Sources of Funding
This work was funded by Blue Cross Blue Shield of Michigan, a
University of Michigan Cardiovascular Center McKay Research
Grant, and an unrestricted educational grant from Bristol-Myers
Squibb, Incorporated. The funding organizations had no role in the
design and conduct of the study; collection, analysis, or preparation
of the data; or preparation, review, or approval of the manuscript.

Disclosures
Dr Gurm received research support from Blue Cross Blue Shield of
Michigan and the National Institutes of Health. Dr Kassab is a
speaker/consultant for Abbott Vascular/Guidant Corporation, Boston
Scientific Corporation, Cardiovascular Systems Inc, ev3/FoxHollow
Corporation, Spectranetics Corporation, and Medtronic Vascular
Corporation, holding stocks in Cardiovascular Systems, Inc, and is
founder/co-owner of Kassab, Kughn, Endovascular, LLC (KKED,
LLC). Dr Grossman received research support from Blue Cross Blue
Shield of Michigan.

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CLINICAL PERSPECTIVE
The optimal degree of heparin anticoagulation for peripheral vascular interventions (PVI) has not been defined. Current
recommendations have been empirically based on data from the coronary literature. We sought to correlate heparin dose
and peak procedural activated clotting time with postprocedural outcomes in patients undergoing PVI in a regional,
multicenter registry. Total heparin dose 60 U/kg and peak activated clotting time 250 seconds were associated with
significantly higher rates of post-PVI drop in hemoglobin 3 g/dL and/or transfusion, with no differences in technical or
procedural success or thromboembolic complications. These findings suggest that weight-based heparin dosing (initially
up to 60 U/kg) with a target activated clotting time of 250 seconds or less may improve outcomes in PVI, with the caveat
that an acceptable lower activated clotting time threshold is unknown. Our study is important because it establishes an
evidence base for the optimal degree of heparin anticoagulation for PVI.

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SUPPLEMENTAL MATERIAL

Participating hospitals in the BMC2 PVI registry:

University of Michigan Health System, Ann Arbor, MI; Veterans Administration Ann Arbor
Medical Center, Ann Arbor, MI; St. Joseph Mercy Hospital, Ann Arbor, MI; Sparrow Hospital,
Lansing, MI; Oakwood Hospital, Dearborn, MI; Meijer Heart Center, Grand Rapids, MI;
Holland Hospital, Holland, MI

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