Thrombosis Research: Tiffany K. Pon, William E. Dager, A. Joshua Roberts, Richard H. White
Thrombosis Research: Tiffany K. Pon, William E. Dager, A. Joshua Roberts, Richard H. White
Thrombosis Research: Tiffany K. Pon, William E. Dager, A. Joshua Roberts, Richard H. White
Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres
Regular Article
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
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 HD patients. Patients were included in the study if they were age
anticoagulation and subsequent bleeding [4–8]. Current practice guide- 18 years or older, required chronic or acute HD, and received at least
lines also state LMWH should be avoided in HD patients; however, one dose of enoxaparin or were started on an UFH continuous infusion.
there have been no prospective studies that have directly assessed Consecutive patients receiving enoxaparin were matched 1:1 with ran-
clinical outcomes of LMWH treatment in this population. Enoxaparin domly selected patients treated with IV UFH, based on the indication for
(Lovenox®, Bridgewater, New Jersey, United States of America) has anticoagulation. Indications included the following: acute VTE, bridging
been shown to accumulate in patients treated with therapeutic doses therapy, VTE prophylaxis following orthopedic surgery or multi-trauma,
(1.0-1.25 mg/kg) given subcutaneously every 12 hours for non-ST- ACS, bridging for cardiac valve replacement, stroke prevention for atrial
segment elevation acute coronary syndrome (ACS), with a strong linear fibrillation/flutter, hypercoagulable state, and cardioversion/ablation
relationship between the creatinine clearance (CrCl) and drug clearance procedures. Patients were excluded if they were treated with a LMWH
[5]. In this study by Becker et al., only 11 of 445 (2.5%) patients in their co- other than enoxaparin, received only prophylactic doses of anti-
hort had impaired renal function, defined as CrCl less than 40 mL/min. coagulation (e.g. enoxaparin 30 mg daily), did not meet matching
Major hemorrhage, a secondary outcome of the study, occurred in 27 of criteria, or if they had incomplete medical records. The study was
445 (6.1%) patients, but it is unclear how many of these patients were approved by the UCDMC Institutional Review Board and requirement
in the impaired renal function group. Importantly, the enoxaparin dose for informed consent was waived.
was not reduced or adjusted for decreased renal function.
A recent study evaluated the use of standard therapeutic doses of Bleeding risk assessment and monitoring
dalteparin and tinzaparin for perioperative bridging in HD patients
and measured trough anti-Xa levels 20–24 hours after dose administra- During chart review, patients were retrospectively assessed for
tion [8]. Patients in this study had chronic renal failure and were receiv- baseline bleeding risk based on the HAS-BLED scoring system [18].
ing intermittent HD three times per week. This study documented Anti-factor Xa levels were not collected as they were not drawn during
accumulation of tinzaparin and dalteparin at non-adjusted therapeutic hospitalization; patients receiving enoxaparin were monitored with
doses in these HD patients; however, the trial was neither designed complete blood counts (CBC) and clinical signs and symptoms of bleed-
nor powered to make any inferences about the safety or efficacy of ing. Patients receiving UFH were monitored using activated partial
treatment using these LMWH preparations, and the authors did not thromboplastin time (APTT) in addition to CBC and clinical signs and
report any clinical outcomes. Routine measurment of plasma anti-Xa symptoms of bleeding. Baseline international normalized ratios (INR)
levels in HD patients or patients with severe renal insufficiency treated were also collected.
with a LMWH has not been validated as a useful or reliable parameter
for monitoring these patients [9]. Outcome measures
Use of LMWH to prevent HD circuit thrombosis has been studied,
and these drugs are commonly used in HD centers [10]. Reports indicate The primary efficacy endpoint was 30-day incidence of a symptom-
that use of enoxaparin is safe and effective when single lower doses of atic thromboembolic event. The primary safety endpoint was 30-day
0.4 to 0.7 mg/kg are delivered intravenously prior to the HD session incidence of International Society on Thrombosis and Haemostasis
[7,11–16]. In a study comparing enoxaparin to regular UFH, a modified (ISTH)-defined major bleeding, which is fatal bleeding and/or symp-
enoxaparin dose of 0.7 mg/kg IV prior to dialysis was shown to be tomatic bleeding in a critical organ or area (e.g. intracranial, intraspinal,
effective in maintaining circuit patency and was associated with a low intraocular, retroperitoneal, intraarticular or pericardial, or intramuscu-
incidence of significant bleeding; however, use of a LMWH for this indi- lar with compartment syndrome) and/or bleeding causing a fall in
cation remains an off-label practice [4,17]. hemoglobin level of 2 g/dL or more, or bleeding leading to transfusion
Seeking alternative parenteral anticoagulation, physicians at the of two or more units of packed red blood cells [19]. Secondary outcomes
University of California, Davis Medical Center (UCDMC) consulted included the 30-day incidence of readmission for any reason, 30-day
with the inpatient anticoagulation service and began treating select all-cause mortality, and hospital length of stay. Readmission and
HD patients with a modified, lower dose of subcutaneous enoxaparin mortality as reported in the UCDMC electronic health record (EHR)
ranging 0.4-1 mg/kg daily. Actual dose selection was based principally were the only late outcome measures; all other endpoints occurred
on assessment of the risk of thrombosis versus the risk of bleeding. during hospitalization.
This lower “adjusted” treatment dose was used for several different
indications including acute VTE, bridging therapy, VTE prophylaxis fol- Statistical analysis
lowing orthopedic surgery or multi-trauma, ACS, bridging for cardiac
valve replacement, stroke prevention for atrial fibrillation/flutter, A sample size calculation to ensure that a 15% difference in major
hypercoagulable state, and cardioversion/ablation procedures. bleeding would be statistically significant indicated that a total of 128
Given the paucity of studies in medical literature that have rigorously patients would be necessary, assuming 80% power and an α = 0.05.
evaluated therapeutic dosing of enoxaparin (Lovenox®) in HD patients, All statistics were performed in Statistical Analysis Software (SAS).
the aim of this retrospective chart review was to compare the safety Continuous variables were tested using the t-test or Kruskal-Wallis
and efficacy of therapeutic subcutaneous enoxaparin versus continuous test. Categorical variables were tested using X2 or Fisher’s Exact. Test
intravenous UFH in patients receiving various forms of HD (e.g. intermit- selection was based on the validity of the normal assumption. A multi-
tent hemodialysis, continuous renal replacement therapy, slow extended variate logistic regression was performed to assess risk factors poten-
daily dialysis, and ultrafiltration). The primary efficacy endpoint was tially associated with major bleeding.
30-day thromboembolic event and the primary safety endpoint was
the 30-day incidence of major bleeding. Results
Study design and patient population 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
This single-center retrospective chart review was conducted to eval- UFH order. After exclusion for various reasons (e.g. order not adminis-
uate the outcomes associated with use of reduced-dose therapeutic tered, prophylactic dosing, missing order, etc.) 89 enoxaparin treated
enoxaparin versus continuous infusion IV UFH for anticoagulation in patients remained to be matched. A total of 164 patients were included
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 3
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 commonly done when intravenous access for UFH continuous infu-
enoxaparin group (20 ± 58.3 vs 28.9 ± 44.5, p = 0.02); there were sion was lost. Given the fact that most of the patients treated with
no differences in mortality or readmission rates (Table 4). enoxaparin had chronic renal failure and were deemed stable for bridg-
In the multivariable logistic regression analysis of risk factors for ing therapy, similar patients are likely the best candidates for treatment
bleeding, the use of enoxaparin was associated with somewhat lower based on the findings of this study. Our findings do not support the use
risk, but this was not statistically significant (OR = 0.77, 95%CI:0.2- of enoxaparin in critically ill or unstable HD patients, nor do they sup-
3.5, p = 0.73). Antiplatelet use was associated with a significant port the use of enoxaparin in patients receiving CRRT.
increase in the risk of bleedinging (OR = 18.9, 95%CI 1.8-200, p = Enoxaparin was the selected LMWH based on the larger range of
0.03), whereas concomitant anticoagulant (i.e. bridging with parenteral available syringe dose sizes, and a review of published experiences in
anticoagulation to warfarin) use was protective (OR = 0.15, 95%CI: literature that have described safe use of intravenously administered
0.03-0.7) (Table 5). 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
Discussion exploring use of LMWH at “treatment” doses uniformly excluded
patients with renal failure who required renal support therapy, and
The most significant finding from this retrospective study was that because the administration of 1 mg/kg once daily in clinical trial
there was no significant difference in the incidence of major bleeding patients who had an estimated CrCl below 30 mL/min was associated
among HD patients treated with therapeutic doses of enoxaparin versus with increased bleeding, the anticoagulation service at UCDMC recom-
IV UFH. However, these results should be interpreted cautiously, and mended that enoxaparin be given in the dose range of 0.5 to 1 mg/kg
it should be stressed that these chronic HD patients were treated with once daily coupled with clinical assessment of the patients risk for
a lower “adjusted” dose of enoxaparin that that averaged 0.7 ± bleeding and thrombosis [4]. Although the HAS-BLED bleeding risk
0.2 mg/kg/day. This dose was comparable to the reported range of score has only been validated to estimate bleeding risk in atrial fibrilla-
intravenous doses of enoxaparin used for dialysis circuit anticoagulation tion patients receiving warfarin therapy, it does account for important
in previous studies [7,11–16]. In most cases, enoxaparin was ordered as risk factors for bleeding [19]. The score was used as an objective
a parenteral bridging agent for the transition to therapeutic warfarin. way to estimate bleeding risk for all patients in the study and showed
This was often done close to time of hospital discharge, but it was also 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)
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 5
Table 3 Table 5
Enoxaparin Usage. Multivariate analysis of bleeding outcome.
Table 4 Conclusion
Outcome measures.
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
6 T.K. Pon et al. / Thrombosis Research xxx (2014) xxx–xxx
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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