TR-05459; No of Pages 6

Thrombosis Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Regular Article

Subcutaneous Enoxaparin for Therapeutic Anticoagulation in

Hemodialysis Patients☆
Tiffany K. Pon a,⁎, William E. Dager b,c,1, A. Joshua Roberts d,e,2, Richard H. White f,3
a
Clinical Pharmacy, University of California, San Francisco, CA, 2315 Stockton Blvd, Sacramento, CA 95815, USA
b
University of California, Davis Medical Center, University of California, San Francisco, CA, USA
c
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

a r t i c l e i n f o a b s t r a c t

Article history: Background: Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anti-
Received 6 January 2014 coagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety
Received in revised form 5 March 2014 and efficacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.
Accepted 18 March 2014 Materials and Methods: This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin
Available online xxxx
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
Keywords:
Heparin
events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and
Low-Molecular-Weight Heparin mortality.
Enoxaparin Results: One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin
Renal Dialysis used to target therapeutic levels was 0.7 ± 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH,
Thromboembolism there was no significant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%,
Hemorrhage 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 significant difference between groups in mortality or readmission. Adjusting for risk factors for bleed-
ing there was a slight but statistically non-significant difference between enoxaparin versus UFH (OR = 0.77, 95%CI:
0.2-3.5, p = 0.73).
Conclusions: These findings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.4-
1 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

Options for full-dose “therapeutic” anticoagulation in patients with

chronic renal failure who require hemodialysis (HD) are limited, with
Abbreviations: IV, intravenous; UFH, unfractionated heparin; LMWH, low-molecular- few alternatives to the gold-standards of intravenous (IV) unfractionated
weight heparins; VTE, venous thromboembolism; ACS, acute coronary syndrome; CrCl,
creatinine clearance; UCDMC, University of California, Davis Medical Center; ISTH,
heparin (UFH) and oral vitamin K antagonists (e.g. warfarin) [1,2].
International Society on Thrombosis and Haemostasis; SAS, Statistical Analysis Nevertheless there are clinical situations when subcutaneously injected
Software; CAD, coronary artery disease; CVA, cerebrovascular accident; IHD, intermittent low-molecular-weight heparins (LMWH) might be potentially advanta-
hemodialysis; CRRT, continuous renal replacement; SLEDD, slow-extended daily dialysis; geous. These include bridging patients onto or off of warfarin (including
PD, peritoneal dialysis.
perioperative bridging), treating patients with absent or poor venous
☆ Research Location: University of California, Davis Medical Center, 2315 Stockton Blvd,
Sacramento, CA 95815. access, and treating cancer patients with acute venous thromboembo-
⁎ Tel.: +1 916 734 7726; fax: +1 916 703 4008. lism (VTE) [3]. Although these scenarios are not common, they are not
E-mail addresses: tiffany.pon@ucsf.edu (T.K. Pon), william.dager@ucdmc.ucdavis.edu rare. A comparison of HD patients treated with UFH versus LMWH
(W.E. Dager), aaron.roberts@ucdmc.ucdavis.edu (A.J. Roberts), rhwhite@ucdavis.edu would be useful to better define the incidence of bleeding and thrombotic
(R.H. White).
1
Tel.: +1 916 703 4025; fax: +1 916 703 5618.
outcomes in patients managed with these drugs.
2
Tel.: +1 916 703 4024; fax: +1 916 703 5618. Because LMWH have reduced renal clearance, large volumes of
3
Te.: +1 916 734 7005; fax: +1 916 734 2732. distribution, and longer half-lives than UFH, the assumed risk of using

http://dx.doi.org/10.1016/j.thromres.2014.03.036
0049-3848/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article as: Pon TK, et al, Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients, Thromb Res (2014),
http://dx.doi.org/10.1016/j.thromres.2014.03.036
2 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx
these drugs in hemodialysis patients is accumulation, excessive
anticoagulation and subsequent bleeding [4–8]. Current practice guide-
lines also state LMWH should be avoided in HD patients; however,
there have been no prospective studies that have directly assessed
clinical outcomes of LMWH treatment in this population. Enoxaparin
(Lovenox®, Bridgewater, New Jersey, United States of America) has
been shown to accumulate in patients treated with therapeutic doses
(1.0-1.25 mg/kg) given subcutaneously every 12 hours for non-ST-
segment elevation acute coronary syndrome (ACS), with a strong linear
relationship between the creatinine clearance (CrCl) and drug clearance
[5]. In this study by Becker et al., only 11 of 445 (2.5%) patients in their co-
hort had impaired renal function, defined as CrCl less than 40 mL/min.
Major hemorrhage, a secondary outcome of the study, occurred in 27 of
445 (6.1%) patients, but it is unclear how many of these patients were
in the impaired renal function group. Importantly, the enoxaparin dose
was not reduced or adjusted for decreased renal function.
A recent study evaluated the use of standard therapeutic doses of
dalteparin and tinzaparin for perioperative bridging in HD patients
and measured trough anti-Xa levels 20–24 hours after dose administra-
tion [8]. Patients in this study had chronic renal failure and were receiv-
ing intermittent HD three times per week. This study documented
accumulation of tinzaparin and dalteparin at non-adjusted therapeutic
doses in these HD patients; however, the trial was neither designed
nor powered to make any inferences about the safety or efficacy of
treatment using these LMWH preparations, and the authors did not
report any clinical outcomes. Routine measurment of plasma anti-Xa
levels in HD patients or patients with severe renal insufficiency treated
with a LMWH has not been validated as a useful or reliable parameter
for monitoring these patients [9].
Use of LMWH to prevent HD circuit thrombosis has been studied,
and these drugs are commonly used in HD centers [10]. Reports indicate
that use of enoxaparin is safe and effective when single lower doses of
0.4 to 0.7 mg/kg are delivered intravenously prior to the HD session
[7,11–16]. In a study comparing enoxaparin to regular UFH, a modified
enoxaparin dose of 0.7 mg/kg IV prior to dialysis was shown to be
effective in maintaining circuit patency and was associated with a low
incidence of significant bleeding; however, use of a LMWH for this indi-
cation remains an off-label practice [4,17].
Seeking alternative parenteral anticoagulation, physicians at the
University of California, Davis Medical Center (UCDMC) consulted
with the inpatient anticoagulation service and began treating select
HD patients with a modified, lower dose of subcutaneous enoxaparin
ranging 0.4-1 mg/kg daily. Actual dose selection was based principally
on assessment of the risk of thrombosis versus the risk of bleeding.
This lower “adjusted” treatment dose was used for several different
indications including acute VTE, bridging therapy, VTE prophylaxis fol-
lowing orthopedic surgery or multi-trauma, ACS, bridging for cardiac
valve replacement, stroke prevention for atrial fibrillation/flutter,
hypercoagulable state, and cardioversion/ablation procedures.
Given the paucity of studies in medical literature that have rigorously
evaluated therapeutic dosing of enoxaparin (Lovenox®) in HD patients,
the aim of this retrospective chart review was to compare the safety
and efficacy of therapeutic subcutaneous enoxaparin versus continuous
intravenous UFH in patients receiving various forms of HD (e.g. intermit-
tent hemodialysis, continuous renal replacement therapy, slow extended
daily dialysis, and ultrafiltration). The primary efficacy endpoint was
30-day thromboembolic event and the primary safety endpoint was
the 30-day incidence of major bleeding.
Materials and methods
Study design and patient population
This single-center retrospective chart review was conducted to eval-
uate the outcomes associated with use of reduced-dose therapeutic
enoxaparin versus continuous infusion IV UFH for anticoagulation in
Please cite this article as: Pon TK, et al, Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients, Thromb Res (2014),
http://dx.doi.org/10.1016/j.thromres.2014.03.036
HD patients. Patients were included in the study if they were age
18 years or older, required chronic or acute HD, and received at least
one dose of enoxaparin or were started on an UFH continuous infusion.
Consecutive patients receiving enoxaparin were matched 1:1 with ran-
domly selected patients treated with IV UFH, based on the indication for
anticoagulation. Indications included the following: acute VTE, bridging
therapy, VTE prophylaxis following orthopedic surgery or multi-trauma,
ACS, bridging for cardiac valve replacement, stroke prevention for atrial
fibrillation/flutter, hypercoagulable state, and cardioversion/ablation
procedures. Patients were excluded if they were treated with a LMWH
other than enoxaparin, received only prophylactic doses of anti-
coagulation (e.g. enoxaparin 30 mg daily), did not meet matching
criteria, or if they had incomplete medical records. The study was
approved by the UCDMC Institutional Review Board and requirement
for informed consent was waived.
Bleeding risk assessment and monitoring
During chart review, patients were retrospectively assessed for
baseline bleeding risk based on the HAS-BLED scoring system [18].
Anti-factor Xa levels were not collected as they were not drawn during
hospitalization; patients receiving enoxaparin were monitored with
complete blood counts (CBC) and clinical signs and symptoms of bleed-
ing. Patients receiving UFH were monitored using activated partial
thromboplastin time (APTT) in addition to CBC and clinical signs and
symptoms of bleeding. Baseline international normalized ratios (INR)
were also collected.
Outcome measures
The primary efficacy endpoint was 30-day incidence of a symptom-
atic thromboembolic event. The primary safety endpoint was 30-day
incidence of International Society on Thrombosis and Haemostasis
(ISTH)-defined major bleeding, which is fatal bleeding and/or symp-
tomatic bleeding in a critical organ or area (e.g. intracranial, intraspinal,
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscu-
lar with compartment syndrome) and/or bleeding causing a fall in
hemoglobin level of 2 g/dL or more, or bleeding leading to transfusion
of two or more units of packed red blood cells [19]. Secondary outcomes
included the 30-day incidence of readmission for any reason, 30-day
all-cause mortality, and hospital length of stay. Readmission and
mortality as reported in the UCDMC electronic health record (EHR)
were the only late outcome measures; all other endpoints occurred
during hospitalization.
Statistical analysis
A sample size calculation to ensure that a 15% difference in major
bleeding would be statistically significant indicated that a total of 128
patients would be necessary, assuming 80% power and an α = 0.05.
All statistics were performed in Statistical Analysis Software (SAS).
Continuous variables were tested using the t-test or Kruskal-Wallis
test. Categorical variables were tested using X2 or Fisher’s Exact. Test
selection was based on the validity of the normal assumption. A multi-
variate logistic regression was performed to assess risk factors poten-
tially associated with major bleeding.
Results
Baseline characteristics
Fig. 1 outlines the entry of patients into the study. A total of 710
patients were identified; 289 had an enoxaparin order and 421 had an
UFH order. After exclusion for various reasons (e.g. order not adminis-
tered, prophylactic dosing, missing order, etc.) 89 enoxaparin treated
patients remained to be matched. A total of 164 patients were included
 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx 3

Fig. 1. Flow diagram for patient selection.

in the analysis with 82 patients in each group. Baseline characteristics (CAD) and diabetes were statistically significantly more prevalent
were similar between groups with respect to demographics (Table 1). in the enoxaparin group. Treatment of VTE was the most common indi-
When comparing baseline comorbidities, coronary artery disease cation for anticoagulation (Fig. 2). The baseline risk for bleeding assess-
ment using the HAS-BLED scoring system showed a similar distribution
Table 1
in risk for enoxaparin treated and heparin treated patients (Fig. 3) [18].
Baseline Characteristics.
Renal and hemodialysis characteristics
Enoxaparin (n = 82) UFH (n = 82) p

Patient Characteristics The majority of patients in both groups had documented chronic
Age Mean ± SD (years) 57 ± 16 55 ± 15 0.5
kidney disease requiring HD; however, significantly more patients
Height Mean ± SD (cm) 167.3 ± 11 167.4 ± 11 0.98
Weight Mean ± SD (kg) 80.4 ± 21 81.8 ± 25 0.72 treated with UFH were admitted with acute kidney injury requiring
Gender n (%) 35 (43) 35 (44) 1 temporary HD (23% vs 7%, p = 0.008) (Table 2). Significantly more
Comorbidities [n (%)] patients in the enoxaparin group received intermittent hemodialysis
Heart Failure 38 (46.3) 30 (36.6) 0.23 when compared to the UFH arm (95.1% vs 84.2%, p = 0.03). A minority
Hypertension 74 (90.2) 64 (78.1) 0.05
of patients (9.7%) received other modes of dialysis, which included
Diabetes 51 (62.2) 35 (42.3) 0.02
History of CVA 14 (17.1) 18 (21.9) 0.55 peritoneal dialysis (PD), slow-extended daily dialysis (SLEDD), and con-
History of ACS 13 (15.7) 9 (10.7) 0.37 tinuous renal replacement therapy (CRRT).
CAD 34 (41.5) 17 (20.7) 0.007
Liver Disease 13 (15.9) 10 (12.2) 0.65
Enoxaparin and UFH usage
Labs (Mean ± SD)
INR 1.49 ± 0.52 1.2 ± 0.31 b0.001
APTT (seconds) 57.9 ± 32 44.5 ± 29 0.02 For the patients receiving enoxaparin, the average number of doses
PLT (k/mm3) 227.1 ± 108 185.3 ± 71.2 0.005 was 3.3 ± 4.2 per subject, (n = 61, range 1–23), and the dose ranged
Total Bilirubin 0.9 ± 0.57 1.6 ± 2.6 0.13 from 0.4 to 1 mg/kg/day, with an average dose of 0.7 ± 0.2 mg/kg/day
Hgb (g/dL) 9.95 ± 1.6 10.5 ± 1.86 0.05
(Table 3). The average duration of therapy for UFH was 8.6 ± 8.8 days,
Hct (%) 30.2 ± 4.8 31.8 ± 5.64 0.06
Vital Signs (Mean ± SD) and the target APTT ranges averaged 69 ± 9.2 seconds for the lower
Temperature (Celsius) 36.7 ± 0.53 36.6 ± 0.63 0.08 target limit to 89.7 ± 9.1 seconds for the upper target limit.
Heart Rate 80 ± 14 89.6 ± 22.9 0.002
Respiratory Rate 18 ± 2.4 18 ± 3.4 0.99
Outcome measures
Systolic Blood Pressure 129.4 ± 26.1 126.5 ± 28.3 0.51
Diastolic Blood Pressure 69.8 ± 15.7 68.4 ± 20.9 0.63
When comparing enoxaparin treated patients to patients treated
Abbreviations – standard deviation (SD), cerebrovascular accident (CVA), acute coronary
syndrome (ACS), coronary artery disease (CAD), international normalized ratio (INR),
with IV UFH, there were no statistically significant differences in the
activated partial thromboplastin time (APTT), platelet (PLT), hemoglobin (Hgb), incidence of either major bleeding (6.1% vs 11%, p = 0.4) or thrombo-
hematocrit (Hct) embolic events (0% vs 2.44%, p = 0.5). With respect to secondary

Please cite this article as: Pon TK, et al, Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients, Thromb Res (2014),
http://dx.doi.org/10.1016/j.thromres.2014.03.036
4 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx

Fig. 2. Indications for Anticoagulation. All indications require treatment doses of anticoagulation. Multiple indications frequently included both atrial fibrillation and VTE treatment. VTE
prophlyaxis refers to post-total knee arthroplasty or post-total hip arthroplasty prophylaxis in which therapeutic anticoagulation levels are targeted.

outcomes, hospital length of stay was significantly shorter in the
enoxaparin group (20 ± 58.3 vs 28.9 ± 44.5, p = 0.02); there were
no differences in mortality or readmission rates (Table 4).
In the multivariable logistic regression analysis of risk factors for
bleeding, the use of enoxaparin was associated with somewhat lower
risk, but this was not statistically significant (OR = 0.77, 95%CI:0.2-
3.5, p = 0.73). Antiplatelet use was associated with a significant
increase in the risk of bleedinging (OR = 18.9, 95%CI 1.8-200, p =
0.03), whereas concomitant anticoagulant (i.e. bridging with parenteral
anticoagulation to warfarin) use was protective (OR = 0.15, 95%CI:
0.03-0.7) (Table 5).
Discussion
The most significant finding from this retrospective study was that
there was no significant difference in the incidence of major bleeding
among HD patients treated with therapeutic doses of enoxaparin versus
IV UFH. However, these results should be interpreted cautiously, and
it should be stressed that these chronic HD patients were treated with
a lower “adjusted” dose of enoxaparin that that averaged 0.7 ±
0.2 mg/kg/day. This dose was comparable to the reported range of
intravenous doses of enoxaparin used for dialysis circuit anticoagulation
in previous studies [7,11–16]. In most cases, enoxaparin was ordered as
a parenteral bridging agent for the transition to therapeutic warfarin.
This was often done close to time of hospital discharge, but it was also
commonly done when intravenous access for UFH continuous infu-
sion was lost. Given the fact that most of the patients treated with
enoxaparin had chronic renal failure and were deemed stable for bridg-
ing therapy, similar patients are likely the best candidates for treatment
based on the findings of this study. Our findings do not support the use
of enoxaparin in critically ill or unstable HD patients, nor do they sup-
port 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 recom-
mended 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 fibrilla-
tion 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 insufficiency and hemodialysis characteristics.

Enoxaparin UFH p
(n = 82) (n = 82)

Type of Renal Failure [n (%)]

Chronic Kidney Disease 75 (93) 63 (77) 0.008
Acute Renal Failure 7 (7) 19 (23)
Hemodialysis Mode [n (%)]
Fig. 3. Bleeding risk assessment using the HASBLED scoring system. HAS-BLED acronym:
Intermittent Hemodialysis (IHD) 78 (95.1) 69 (84.2) 0.03
Hypertension (uncontrolled, N160 mmHg systolic), Abnormal renal/liver function, Stroke,
Slow Extended Daily Dialysis (SLEDD) 2 (2.41) 6 (7.32) 0.28
Bleeding history or predisposition (anemia), Labile INR (i.e. therapeutic time in range
Continuous Renal Replacement Therapy (CRRT) 0 (0) 4 (4.88) 0.12
b60%), Elderly (N65 years), and Drugs/alcohol concomitantly (e.g. antiplatelet agents,
Peritoneal Dialysis (PD) 2 (2.41) 3 (3.66) 1
non-steroidal anti-inflammatory drugs). Maximum score = 9.

Please cite this article as: Pon TK, et al, Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients, Thromb Res (2014),
http://dx.doi.org/10.1016/j.thromres.2014.03.036
 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx
Table 3
Enoxaparin Usage.
Average number of doses (n = 61)
Mean ± SD 3.3 ± 4.2
Dose range (mg/kg/day) 0.4 – 1
Average dose (mg/kg/day)
Mean ± SD 0.7 ± 0.2
were associated with a reduction in minor bleeding and no notable
change in thrombosis rates [13]. Furthermore, Chan et al. observed in
a recent retrospective analysis of patients requiring chronic HD that
use of prophylactic subcutaneous enoxaparin in a dose of 30 mg had a
similar incidence of serious bleeding compared to HD patients treated
with higher doses of 31 to 60 mg, suggesting that the risk of bleeding
is minimally increased when doses of 31-60 mg are used; it should be
noted that this study excluded patients with lower body weight [21].
The use of anti-factor Xa activity levels to adjust dosing was not incor-
porated into management decisions because of a reported discordance
between anti-Xa levels and other markers of thrombin generation and
a poor correlation with renal function in both HD and non-dialysis
dependent patients with chronic renal insufficiency [7,22–26]. Studies
have failed to show a consistent relationship between anti-Xa levels
and bleeding [2]. In addition to lack of correlation to a biological effect,
other factors in this population that affect thrombosis or bleeding
may be present, further limiting the value of measuring and adjusting
the dose of LMWH using anti-factor Xa values. [10,20] Monitoring of
enoxaparin in the current study was based only on clinical assessment,
complete blood counts (CBC), and other signs and symptoms of bleeding
or thrombosis.
The study was not sufficiently powered to interpret efficacy of
enoxaparin treatment; however, the incidence of major bleeding in
the enoxaparin group was unexpectedly low, and not significantly
different compared to the UFH group, suggesting an acceptable safety
profile. In the multivariable analysis, the adjusted risk of major bleeding
was slightly but not statistically significantly reduced in patients treated
with enoxaparin. Cosette and colleagues were able to demonstrate that
use of therapeutic UFH was associated with a higher risk of bleeding in a
univariate analysis [27]. This suggests that further study with a larger
sample size may show a statistically significant protective effect of
enoxaparin in HD patients. Also, in the multivariable analysis, the obser-
vation that transitioning enoxaparin to warfarin was protective against
bleeding appears counterintuitive. This may have occurred because of
the large number of patients in the study were being bridged to warfa-
rin therapy and may have receive anticoagulation for a shorter time
period and have a shorter duration of exposure to heparin or LMWH.
In addition to its retrospective design, this study was subject to other
limitations. Matching was limited to one criterion, anticoagulation indi-
cation, in order to achieve an adequate sample size, which led to exclu-
sion of patients treated with UFH. However, without requiring matching
based on the indication for anticoagulation we felt the study would have
been even more limited. The groups were relatively similar with respect
Table 4
Outcome measures.
Enoxaparin UFH p Despite the limitations of a retrospective observational study, this
(n = 82) (n = 82)
Primary Endpoints [n (%)]
30-Day ISTH Major Bleeding 5 (6.1) 9 (11) 0.4
30-Day Thromboembolic Event or 0 2 (2.44) 0.5
Dialysis Catheter Clotting
Secondary Endpoints
Hospital Length of Stay (Days)
Mean ± SD 20 ± 58.3 28.9 ± 44.5 0.02
30-Day Mortality n (%) 5 (6.1) 12 (14.6) 0.12
30-Day Readmission n (%) 17 (20.7) 20 (24.4) 0.7
Please cite this article as: Pon TK, et al, Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients, Thromb Res (2014),
http://dx.doi.org/10.1016/j.thromres.2014.03.036
5
Table 5
Multivariate analysis of bleeding outcome.
Odds Ratio 95% CI p
Treatment (enoxaparin vs UFH) 0.8 0.17, 3.5 0.73
Age 0.98 0.9, 1.04 0.59
Female gender 1.6 0.3, 8.1 0.56
Hgb/Hct 2.4 0.43, 13.1 0.32
Chronic renal insufficiency 12.1 0.6, 2.3 0.09
History of CVA 3.2 0.6, 17.5 0.18
Liver disease 2.8 0.4, 19.2 0.30
Concomitant oral anticoagulant 0.15 0.03, 0.74 0.02
Antiplatelet therapy 18.9 1.8, 200 0.03
to baseline demographics and comorbidities, differing only in a higher
frequency of diabetes and CAD, which put the enoxaparin arm at a
potential increased risk for thrombotic events such as stroke; however,
there were no such complications. Coagulation laboratory parameters
collected at baseline were difficult to interpret as fewer patients in the
enoxaparin (Lovenox®) group had complete labs ordered. Ten patients
in the enoxaparin arm did not have baseline INRs documented, and less
than half had an APTT drawn; however, it is logical that APTT was not
collected as it is not an appropriate monitoring parameter for LMWH.
Regardless, coagulation parameters collected actually suggested the
enoxaparin arm was at an increased risk for bleeding.
With respect to HD and renal characteristics, more patients in the
UFH group had acute kidney injury and required continuous renal
replacement. No patients in the enoxaparin group underwent continu-
ous renal replacement as a hemodialysis modality. This may suggest
that patients in the UFH group had a greater severity of illness, which
could have accounted for the longer hospital length of stay. The initial
intention for including length of stay as a secondary outcome was the
thought that for some patients, having enoxaparin as a bridging option
would expedite their discharge. However, given the numerous con-
founders, no such conclusion can be made. Furthermore, because criti-
cally ill patients receiving acute HD and CRRT in this study did not
receive enoxaparin (Lovenox®) for therapeutic anticoagulation, its use
should be reserved for more stable HD patients.
Exact duration of enoxaparin therapy was also a limitation of the
study. Again, given the retrospective design, we were only able to eval-
uate what was documented in the EHR, and if patients were discharged
on enoxaparin without receiving their first dose in the hospital, we were
unable to capture the exact duration of therapy. As such we were able to
collect this information on only 61 patients in the enoxaparin arm, and
the inpatient exposure days ranged from 1 to 23. Furthermore, we were
only able to assess bleeding in hospitalized patients and in patients who
were readmitted for major bleeding to UCDMC. There is potential that pa-
tients could have been treated for major bleeding at an outside hospital;
however, this potential is equal for both the enoxaparin and UFH arms.
This may actually be reflective of real world limitations of discharging
patients on medications. Finally, if patients were re-admitted to any out-
side hospitals for thrombotic or bleeding events after being exposed to
enoxaparin (Lovenox®), we were unable to capture those admissions
since the study was limited to a single center.
Conclusion
study is the first to evaluate the safety of using enoxaparin for therapeu-
tic anticoagulation in HD patients. The findings suggests that reduced
doses of dose enoxaparin are safe to use in patients on chronic HD
who require therapeutic anticoagulation and not simply a low fixed
dose of 30 mg a day to prevent venous thromboembolism. The findings
also suggest that enoxaparin given at a dose of 0.4-1.0 mg/kg once daily
is a viable option in patients on intermittent HD who are not able to
receive heparin because of the inability to monitor or have IV access
issues. Additionally, use of enoxaparin may be useful as a short term
6 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx
home management option in hemodialysis patients who are otherwise
stable and no longer require hospitalization. Further studies are needed
to determine if efficacy of enoxaparin therapy is safe in critically ill
patients who require acute renal replacement therapy, including con-
tinuous renal replacement therapy. Finally, the encouraging finding
that use of enoxaparin did not result in a higher incidence of bleeding
compared to regular IV heparin needs to be validated in additional
studies. Antiplatelet therapy should be avoided, when possible, in
hemodialysis patients who require therapeutic anticoagulation with a
heparin preparation.
Conflict of interest statement
This study was not funded, and the authors have no disclosures.
Acknowledgments
Machelle Wilson, PhD – for her assistance with statistical analysis.
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