Full text of DOI:10.1592/phco.21.11.1017.34514

Low-Molecular-Weight Heparin Administration in Patients
with End-Stage Renal Disease—A Comment
James Lile, Pharm.D.
(
Pharmacotherapy 2001;21(8):1017–1019)
1
The data presented by Brophy and colleagues
are a good beginning to our understanding of the
pharmacokinetics of enoxaparin in patients
requiring dialysis. Still, there are too many
unanswered questions based on the small
number of patients, administration of a single
dose of enoxaparin, and pharmacokinetic
simulation used to support their conclusions.
References
1
2
3
. Brophy DF, Wazny LD, Gehr TWB, Comstock TJ, Ventiz J.
The pharmacokinetics of subcutaneous enoxaparin in end-stage
renal disease. Pharmacotherapy 2001;21:169–74.
. Duplaga BA, Rivers CW, Nutescu E. Dosing and monitoring of
low-molecular-weight heparins in special populations.
Pharmacotherapy 2001;21:218–34.
. Gerlach AP, Pickworth KK, Seth SK, Tanna SB, Barnes JF.
Enoxaparin and bleeding complications: a review in patients
with and without renal insufficiency. Pharmacotherapy
2000;20:771–5.
2
Other researchers discussed the use of low-
molecular-weight heparins (LMWHs) in patients
with renal insufficiency. Patients with impaired
renal function who receive multiple doses of
LMWH have higher anti-Xa levels, reduced drug
clearances, and prolonged drug half-lives. Clear
guidelines on dosage adjustments for LMWHs
given to patients with end-stage renal disease
Authors’ Reply
1
We are pleased that our article generated
important discussion on the pharmacokinetics of
enoxaparin in patients with end-stage renal
disease (ESRD). We thank Dr. Lile and Drs.
Kalus and Spencer for their commentaries, as
they reemphasize the limitations of our study.
We first want to provide a correction to our
data. Due to a typographical error on page 173,
line 12, we incorrectly reported the weight-based
apparent clearance (Cl/F) and range as 0.13
ml/minute/kg and 0.13–0.25 ml/minute/kg,
respectively. The correct Cl/F should have read
(
ESRD) have not been published.
Investigators retrospectively evaluated the
frequency of bleeding and use of blood products
in patients with renal insufficiency compared
with those with normal renal function who
3
received multiple doses of LMWH. Patients
with renal insufficiency were more likely to have
bleeding complications and require transfusions
than those with normal renal function. Our own
0
.19 ml/minute/kg, and the reported range
should have read 0.14–0.33 ml/minute/kg. This
error does not affect the conclusion that our data
(
limited, unpublished) experience using multiple
doses of LMWH in patients with renal dysfunction
led us to believe that these patients are at higher
risk for hemorrhage compared with patients with
normal renal function.
2
are similar to those reported in another study.
Dr. Lile restated the main talking points listed
in our discussion. In addition, he cites a
3
published review article that describes the
As very few patients receive a single
therapeutic dose of LMWH, it is premature to
state that monitoring and dosing adjustments are
unnecessary in patients with ESRD who receive
multiple doses of LMWH.
literature of various low-molecular-weight
heparins (LMWHs) and their need for dosage
adjustment in patients with renal dysfunction.
His commentary states, “Patients with impaired
renal function who receive multiple doses of
LMWH have higher anti-Xa levels, reduced drug
clearances, and prolonged drug half-lives.” This
statement may be only partly supported by the
literature. In fact, this review article cited only
From the Department of Pharmacy, MidMichigan Health,
4
005 Orchard Drive, Midland, Michigan.
Address correspondence to James Lile, Pharm.D.,
Department of Pharmacy, MidMichigan Health, 4005
Orchard Drive, Midland, MI 48670.

1
018
PHARMACOTHERAPY Volume 21, Number 8, 2001
one multiple-dose study involving nadroparin
that was conducted in elderly subjects with
presumed age-related renal dysfunction. There
are several problems with this study that make it
difficult to interpret its clinical significance. For
example, it was not conducted in patients with
ESRD; the elderly group in this study had a mean
Table 1. Predicted Peak Anti-factor Xa Concentrations at
Steady-State
4
Predicted Peak Anti-Factor Xa
Subject No.
Concentration
1
2
3
4
5
6
7
8
1.17
1.12
0.98
1.23
0.91
0.96
1.22
1.23
creatinine clearance (Cl ) of 62 ml/minute,
cr
which is hardly renal dysfunction. Second,
although the trough anti-factor Xa concentration
for the elderly group (mean 0.20 IU/ml) is
statistically different than that of the young,
healthy group (mean 0.08 IU/ml), both
concentrations are well below the therapeutic
range at the end of therapy. Although this
difference may be statistically significant, it is
likely not clinically relevant.
Mean (95% CI)
Median
CV (%)
1.10 (0.99–1.21)
1.15
12
CI = confidence interval; CV = coefficient of variation.
Another study assessed anti-factor Xa
concentrations of tinzaparin after 10 days of
dosing in patients with age-related renal
function group (2%). Clearly, further study is
necessary.
Drs. Kalus and Spencer raise many good points
on which we would like to elaborate. Single-dose
pharmacokinetic studies often are used to collect
pilot data to aid in developing subsequent
multiple-dose studies. This was the intention of
our study. We agree that our results do not
provide the final answer to this question but, in
fact, are preliminary data to help begin the
process of answering the question.
5
dysfunction. Patients were grouped according to
their creatinine clearances: group 1, Cl > 50
cr
ml/minute; group 2, Cl 40–49 ml/minute group
cr
;
3
, Cl 30–39 ml/minute; and group 4, Cl 20–29
cr cr
ml/minute. All subjects received 10 days of
therapeutic tinzaparin dosing (175 IU/kg
subcutaneously once/day).
The results
demonstrated that there was no accumulation of
tinzaparin in patients with age-related renal
dysfunction. There were no intergroup or
intragroup differences in the mean peak anti-
factor Xa concentrations measured on days 2, 5,
Second, Drs. Kalus and Spencer correctly point
out that the therapeutic range for anti-factor Xa
concentrations is defined only for 4 hours after
the dose of LMWH (peak concentration). Our
study reported the average steady-state
concentration data for the entire dosing interval.
The predicted steady-state peak concentration at
4 hours can be estimated crudely from our data
by simply multiplying the observed peak after a
single dose by the accumulation ratio of 1.6
(Table 1). This calculation yields a mean
estimated peak steady-state anti-factor Xa
concentration of approximately 1.10 IU/ml (95%
confidence interval 0.99–1.21), which is at the
upper end of the therapeutic range at our
institution (0.50–1.20 IU/ml). Three of the eight
subjects are predicted to have peak steady-state
anti-factor Xa concentrations slightly above the
therapeutic range. The clinical implications of
this are unknown since hemorrhagic events have
not been correlated to supratherapeutic anti-
7
and 10 of therapy, and none of the subjects
recorded a supratherapeutic anti-factor Xa
concentration throughout the duration of the
study. Finally, there was no correlation between
creatinine clearance and anti-factor Xa
concentration.
Dr. Lile mentions his personal experience with
bleeding episodes in patients with ESRD and
6
cites a retrospective chart review. As we
discussed in our paper, bleeding is not
uncommon in this population, which already is
prone to bleeding episodes due to their
underlying uremic state. These patients often
require transfusions for many reasons, including
blood loss through dialysis and anemia of
chronic renal failure. We urge caution in trying
to draw firm conclusions from this retrospective
6
7, 8
chart review.
Although these data are
factor Xa concentrations.
suggestive, there are many potential explanations
for the increased bleeding rates in the subjects
with renal insufficiency observed in the chart
review, including more frequent surgeries (25%
of patients) compared with the normal renal
Finally, Drs. Kalus and Spencer suggest that the
coefficient of variation (CV) for the reported
apparent clearance (32%), half-life (41%), and
volume of distribution (32%) is “marked.” We
respectfully disagree and believe that their point

ALTERNATIVE VIEWPOINTS Lile
1019
(
nadroparin). Thromb Haemost 1998;79:1162–5.
is overstated. Generally, a CV of 30% or less in
human studies is considered low variability;
5
6
7
8
9
. Siguret V, Pautas E, Fevrier M, et al. Elderly patients treated
with tinzaparin (Innohep®) administered once daily (175 anti-
Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb
Haemost 2000;84:800–4.
. Gerlach AT, Pickworth KK, Seth SK, Tanna SB, Barnes JF.
Enoxaparin and bleeding complications: a review in patients
with and without renal insufficiency. Pharmacotherapy
3
0–40% variability is moderate and certainly
acceptable. Our CV data are consistent with
other trials
2
, 9, 10
cited in our article.
In summary, our pilot study provided
preliminary data for designing further clinical
trials of enoxaparin in patients with ESRD. We
acknowledge the limitations of our single-dose
study, and we agree that further research is
needed to develop more specific enoxaparin
dosing guidelines in patients with ESRD.
2
000;20:771–5.
. Leizorovicz A, Bara L, Samama MM, Haugh MC. Factor Xa
inhibition: correlation between the plasma levels of anti-Xa
activity and occurrence of thrombosis and haemorrhage.
Haemostasis 1993;23(suppl 1):89–98.
. Matthiasson SE, Lindblad B, Stjernquist U, Bergqvist D. The
haemorrhagic effect of low molecular weight heparins,
dermatan sulphate and hirudin. Haemostasis 1995;25(5):
2
03–11.
. Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F,
Samama MM. The antithrombotic activity and pharmaco-
kinetics of enoxaparine, a low molecular weight heparin, in
humans given 20 to 80 mg. J Clin Pharmacol 1988;28:609–18.
0. Frydman A. Low-molecular weight heparins: an overview of
their pharmacodynamics, pharmacokinetics and metabolism in
humans. Haemostasis 1996;26(suppl 2):24–38.
References
1
2
3
4
. Brophy DF, Wazny LD, Gehr TWB, Comstock TJ, Venitz J.
The pharmacokinetics of subcutaneous enoxaparin in end-stage
renal disease. Pharmacotherapy 2001;21:169–74.
. Cadroy Y, Pourrat J, Baladre MF, et al. Delayed elimination of
enoxaparine in patients with chronic renal insufficiency.
Thromb Res 1991;63(3):385–90.
. Duplaga BA, Rivers CW, Nutescu E. Dosing and monitoring of
low-molecular-weight heparins in special populations.
Pharmacotherapy 2001;21:218–34.
. Mismetti P, Laporte-Simitsidis S, Navarro C, et al. Aging and
VRE influence the pharmacodynamics of the anti-Xa and anti-
thrombin activities of a low molecular weight heparin
1
Donald F. Brophy, Pharm.D.
Lori D. Wazny, Pharm.D.
Todd W. B. Gehr, M.D.
Thomas J. Comstock, Pharm.D.
Jürgen Venitz, M.D., Ph.D.