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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres
Regular Article
Clinical Pharmacy, University of California, San Francisco, CA, 2315 Stockton Blvd, Sacramento, CA 95815, USA
University of California, Davis Medical Center, University of California, San Francisco, CA, USA
University of California, Davis School of Medicine, Touro Vallejo School of Pharmacy, 2315 Stockton Blvd, Sacramento, CA 95815, USA
d
University of California, Davis Medical Center, Clinical Pharmacy, University of California, San Francisco, CA, USA
e
University of California, Davis School of Medicine, 2315 Stockton Blvd, Sacramento, CA 95815, USA
f
Department of Internal Medicine, University of California, Davis Medical Center, Sacramento, CA, USA
b
c
a r t i c l e
i n f o
Article history:
Received 6 January 2014
Received in revised form 5 March 2014
Accepted 18 March 2014
Available online 24 March 2014
Keywords:
Heparin
Low-Molecular-Weight Heparin
Enoxaparin
Renal Dialysis
Thromboembolism
Hemorrhage
a b s t r a c t
Background: Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anticoagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety
and efcacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.
Materials and Methods: This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin
that were matched based on the indication for anticoagulation with patients treated with intravenous UFH
to achieve therapeutic anticoagulation. Primary outcome measures included 30-day incidence of thromboembolic
events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and
mortality.
Results: One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin
used to target therapeutic levels was 0.7 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH,
there was no signicant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%,
p = 0.5). Hospital length of stay was shorter in the enoxaparin group (20 53.8 vs 28.9 44.5 days, p = 0.02);
there was no signicant difference between groups in mortality or readmission. Adjusting for risk factors for bleeding there was a slight but statistically non-signicant difference between enoxaparin versus UFH (OR = 0.77, 95%CI:
0.2-3.5, p = 0.73).
Conclusions: These ndings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.41 mg/kg/day, was as safe as intravenous UFH in providing therapeutic anticoagulation in stable patients requiring
chronic hemodialysis.
2014 Elsevier Ltd. All rights reserved.
Introduction
Abbreviations: IV, intravenous; UFH, unfractionated heparin; LMWH, low-molecularweight heparins; VTE, venous thromboembolism; ACS, acute coronary syndrome; CrCl,
creatinine clearance; UCDMC, University of California, Davis Medical Center; ISTH,
International Society on Thrombosis and Haemostasis; SAS, Statistical Analysis
Software; CAD, coronary artery disease; CVA, cerebrovascular accident; IHD, intermittent
hemodialysis; CRRT, continuous renal replacement; SLEDD, slow-extended daily dialysis;
PD, peritoneal dialysis.
Research Location: University of California, Davis Medical Center, 2315 Stockton Blvd,
Sacramento, CA 95815.
Tel.: +1 916 734 7726; fax: +1 916 703 4008.
E-mail addresses: tiffany.pon@ucsf.edu (T.K. Pon), william.dager@ucdmc.ucdavis.edu
(W.E. Dager), aaron.roberts@ucdmc.ucdavis.edu (A.J. Roberts), rhwhite@ucdavis.edu
(R.H. White).
1
Tel.: +1 916 703 4025; fax: +1 916 703 5618.
2
Tel.: +1 916 703 4024; fax: +1 916 703 5618.
3
Te.: +1 916 734 7005; fax: +1 916 734 2732.
http://dx.doi.org/10.1016/j.thromres.2014.03.036
0049-3848/ 2014 Elsevier Ltd. All rights reserved.
1024
Baseline Characteristics
Fig. 1 outlines the entry of patients into the study. A total of 710
patients were identied; 289 had an enoxaparin order and 421 had an
UFH order. After exclusion for various reasons (e.g. order not administered, prophylactic dosing, missing order, etc.) 89 enoxaparin treated
patients remained to be matched. A total of 164 patients were included
This single-center retrospective chart review was conducted to evaluate the outcomes associated with use of reduced-dose therapeutic
enoxaparin versus continuous infusion IV UFH for anticoagulation in
1025
Patient Characteristics
Age Mean SD (years)
Height Mean SD (cm)
Weight Mean SD (kg)
Gender n (%)
Comorbidities [n (%)]
Heart Failure
Hypertension
Diabetes
History of CVA
History of ACS
CAD
Liver Disease
Labs (Mean SD)
INR
APTT (seconds)
PLT (k/mm3)
Total Bilirubin
Hgb (g/dL)
Hct (%)
Vital Signs (Mean SD)
Temperature (Celsius)
Heart Rate
Respiratory Rate
Systolic Blood Pressure
Diastolic Blood Pressure
Enoxaparin (n = 82)
UFH (n = 82)
57 16
167.3 11
80.4 21
35 (43)
55 15
167.4 11
81.8 25
35 (44)
0.5
0.98
0.72
1
38 (46.3)
74 (90.2)
51 (62.2)
14 (17.1)
13 (15.7)
34 (41.5)
13 (15.9)
30 (36.6)
64 (78.1)
35 (42.3)
18 (21.9)
9 (10.7)
17 (20.7)
10 (12.2)
0.23
0.05
0.02
0.55
0.37
0.007
0.65
1.49 0.52
57.9 32
227.1 108
0.9 0.57
9.95 1.6
30.2 4.8
1.2 0.31
44.5 29
185.3 71.2
1.6 2.6
10.5 1.86
31.8 5.64
b0.001
0.02
0.005
0.13
0.05
0.06
36.7 0.53
80 14
18 2.4
129.4 26.1
69.8 15.7
36.6 0.63
89.6 22.9
18 3.4
126.5 28.3
68.4 20.9
0.08
0.002
0.99
0.51
0.63
1026
Fig. 2. Indications for Anticoagulation. All indications require treatment doses of anticoagulation. Multiple indications frequently included both atrial brillation and VTE treatment. VTE
prophlyaxis refers to post-total knee arthroplasty or post-total hip arthroplasty prophylaxis in which therapeutic anticoagulation levels are targeted.
commonly done when intravenous access for UFH continuous infusion was lost. Given the fact that most of the patients treated with
enoxaparin had chronic renal failure and were deemed stable for bridging therapy, similar patients are likely the best candidates for treatment
based on the ndings of this study. Our ndings do not support the use
of enoxaparin in critically ill or unstable HD patients, nor do they support the use of enoxaparin in patients receiving CRRT.
Enoxaparin was the selected LMWH based on the larger range of
available syringe dose sizes, and a review of published experiences in
literature that have described safe use of intravenously administered
enoxaparin 0.7 mg/kg given prior to HD in order to prevent thrombosis
of the dialysis circuit at the time [20]. Because randomized clinical trials
exploring use of LMWH at treatment doses uniformly excluded
patients with renal failure who required renal support therapy, and
because the administration of 1 mg/kg once daily in clinical trial
patients who had an estimated CrCl below 30 mL/min was associated
with increased bleeding, the anticoagulation service at UCDMC recommended that enoxaparin be given in the dose range of 0.5 to 1 mg/kg
once daily coupled with clinical assessment of the patients risk for
bleeding and thrombosis [4]. Although the HAS-BLED bleeding risk
score has only been validated to estimate bleeding risk in atrial brillation patients receiving warfarin therapy, it does account for important
risk factors for bleeding [19]. The score was used as an objective
way to estimate bleeding risk for all patients in the study and showed
patients receiving enoxaparin had a similar risk as those receiving
UFH. Patients at high risk for bleeding and/or low risk for thrombosis
received a dose at the lower end of the recommended range whereas
patients with high risk for thrombosis and/or lower bleeding risk
received doses at the higher end.
The dosing range selection used in this study was further supported
by an analysis by Saltissi et al. in which dosing reductions from 1 mg/kg
to 0.69 mg/kg of intravenous enoxaparin administered pre-dialysis
Table 2
Renal insufciency and hemodialysis characteristics.
Fig. 3. Bleeding risk assessment using the HASBLED scoring system. HAS-BLED acronym:
Hypertension (uncontrolled, N160 mmHg systolic), Abnormal renal/liver function, Stroke,
Bleeding history or predisposition (anemia), Labile INR (i.e. therapeutic time in range
b60%), Elderly (N65 years), and Drugs/alcohol concomitantly (e.g. antiplatelet agents,
non-steroidal anti-inammatory drugs). Maximum score = 9.
Enoxaparin
(n = 82)
UFH
(n = 82)
75 (93)
7 (7)
63 (77)
19 (23)
0.008
78 (95.1)
2 (2.41)
0 (0)
2 (2.41)
69 (84.2)
6 (7.32)
4 (4.88)
3 (3.66)
0.03
0.28
0.12
1
Table 5
Multivariate analysis of bleeding outcome.
3.3 4.2
0.4 1
0.7 0.2
Table 4
Outcome measures.
1027
Odds Ratio
95% CI
0.8
0.98
1.6
2.4
12.1
3.2
2.8
0.15
18.9
0.17, 3.5
0.9, 1.04
0.3, 8.1
0.43, 13.1
0.6, 2.3
0.6, 17.5
0.4, 19.2
0.03, 0.74
1.8, 200
0.73
0.59
0.56
0.32
0.09
0.18
0.30
0.02
0.03
Enoxaparin
(n = 82)
UFH
(n = 82)
5 (6.1)
0
9 (11)
2 (2.44)
0.4
0.5
20 58.3
5 (6.1)
17 (20.7)
28.9 44.5
12 (14.6)
20 (24.4)
0.02
0.12
0.7
1028
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