Review

Annals of Internal Medicine

Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients

with Severe Renal Insufficiency
Wendy Lim, MD, BSc; Francesco Dentali, MD; John W. Eikelboom, MBBS; and Mark A. Crowther, MD, MSc

Background: Dose adjustment or laboratory monitoring of lowmolecular-weight heparin (LMWH) is commonly recommended for
patients with severe renal insufficiency (creatinine clearance 30
mL/min), but the basis for this recommendation is unclear.
Purpose: To compare levels of anti-Xa heparin and risk for major
bleeding in LMWH-treated patients with a creatinine clearance of
30 mL/min or less versus those with a creatinine clearance greater
than 30 mL/min by using standard weightadjusted therapeutic
doses, empirically adjusted doses, or prophylactic doses of LMWH.
Data Sources: Electronic databases (MEDLINE, EMBASE, and the
Cochrane Library) searched to December 2005 with no language
restrictions. The authors also searched reference lists and contacted
experts.
Study Selection: Observational or subgroups of randomized studies
that included non dialysis-dependent patients with varying degrees
of renal function who were treated with LMWH and reported
creatinine clearance and anti-Xa levels or major bleeding.
Data Extraction: Two reviewers independently selected studies and
extracted data on patient characteristics, renal function, LMWH
treatment, anti-Xa levels, and major bleeding. The pooled odds
ratio of major bleeding in patients with a creatinine clearance of 30
mL/min or less was calculated by using the Peto method.
Data Synthesis: Eighteen studies using 3 preparations of LMWH
(15 studies using enoxaparin, 2 using tinzaparin, and 1 using dalteparin) were included. Peak anti-Xa levels measured 4 hours after a
subcutaneous injection were statistically significantly higher in patients with a creatinine clearance of 30 mL/min or less compared
with those with a creatinine clearance greater than 30 mL/min in

ne of the most important advantages of low-molecular-weight heparin (LMWH) compared with unfractionated heparin (UFH) is its predictable anticoagulant
response, which allows it to be administered in fixed,
weight-based doses without laboratory monitoring. When
used to treat patients with acute venous thromboembolism,
LMWH is associated with lower rates of recurrent thrombosis, bleeding, and death than is weight-adjusted, monitored UFH (1, 2). These advantages have revolutionized
management of acute venous thromboembolism by allowing most patients to be treated out of hospital. Low-molecular-weight heparin has also greatly simplified in-hospital management of selected patients with venous
thromboembolism and those with acute coronary syndromes. However, uncertainty still surrounds use of
LMWH in patients with severe renal insufficiency because
it is excreted by the kidneys (3) and, unlike UFH, its anticoagulant effect cannot be completely reversed. Although
most randomized trials of LMWH excluded patients with
renal insufficiency (4), pharmacokinetic studies suggest an

studies that used a standard therapeutic dose of enoxaparin (4

studies) but not in studies of empirically dose-adjusted enoxaparin
(3 studies). Data were insufficient to assess the relationship between anti-Xa and renal function for prophylactic doses of enoxaparin and therapeutic doses of tinzaparin or dalteparin. In 12
studies involving 4971 patients, LMWH was associated with a
statistically significant increase in the risk for major bleeding in
patients with a creatinine clearance of 30 mL/min or less compared
with those with a creatinine clearance greater than 30 mL/min
(5.0% vs. 2.4%; odds ratio, 2.25 [95% CI, 1.19 to 4.27]; P
0.013). When analyzed according to LMWH preparation, major
bleeding was increased when a standard therapeutic dose of enoxaparin was used (8.3% vs. 2.4%; odds ratio, 3.88 [CI, 1.78 to
8.45]) but may not be increased when an empirically adjusted dose
of enoxaparin is used (0.9% vs. 1.9%; odds ratio, 0.58 [CI, 0.09 to
3.78]; P 0.23 for heterogeneity). There were insufficient studies
to assess the risk for major bleeding with tinzaparin, dalteparin, and
prophylactic doses of enoxaparin.
Limitations: The data for tinzaparin and dalteparin were limited.
Data are observational, and the potential for confounding cannot
be excluded.
Conclusions: Non dialysis-dependent patients with a creatinine
clearance of 30 mL/min or less who are treated with standard
therapeutic doses of enoxaparin have elevated levels of anti-Xa and
an increased risk for major bleeding. Empirical dose adjustment of
enoxaparin may reduce the risk for bleeding and merits additional
evaluation. No conclusions can be made regarding other LMWHs.
Ann Intern Med. 2006;144:673-684.
For author affiliations, see end of text.

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association between creatinine clearance and levels of antifactor Xa heparin (which measures the anticoagulant effect
of LMWH), and increased bleeding complications have
been reported when LMWH is used in patients with
chronic renal insufficiency (5, 6).
Because of concerns about the risk for accumulation
and bleeding in patients with renal impairment, the American College of Chest Physicians and the College of American Pathologists recommend UFH instead of LMWH in

See also:
Print
Editors Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
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Appendix
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Review

Low-Molecular-Weight Heparin in Renal Insufficiency

Context
The risks of low-molecular-weight heparin (LMWH) in patients with severe renal insufficiency are not clear.

Contribution
In this review of 12 studies, patients with severe renal insufficiency receiving LMWH had an increased risk for major bleeding events. Four studies found that fixed-dose
enoxaparin had greater anticoagulant effects in these patients. Three studies suggested that empirically dose-adjusted enoxaparin might not increase anticoagulant effects.

Cautions
Evidence relating to LMWHs other than enoxaparin was
scant.

Implications
Patients with severe renal insufficiency receiving standard
fixed-dose enoxaparin have greater anticoagulant effects
and a higher risk for major bleeding. Empirical dose adjustment may reduce the risk for such events.
The Editors

databases. The search was completed on 19 December

2005. The search strategy, which had no language restrictions, was developed in collaboration with a professional
librarian (Appendix, available at www.annals.org). We
manually reviewed the reference lists of all retrieved articles
and contacted content experts for additional published or
unpublished trials.
Study Selection

Study selection was performed independently and in

duplicate; disagreements were resolved through discussion.
Studies were included if they 1) had at least 10 patients; 2)
involved patients with varying degrees of renal function,
including those with a creatinine clearance of 30 mL/min
or less; 3) administered at least 1 dose of a commercially
available LMWH; and 4) reported at least 1 of the following outcomes: anti-Xa levels or major bleeding. Studies
were excluded if patients were dialysis-dependent, if
LMWH was administered intravenously, if more than 1
LMWH preparation or dose (for example, prophylactic
and therapeutic doses) were used, and if the data for anti-Xa or bleeding for individual LMWH preparations or
doses could not be separately analyzed.
Study Quality Assessment

patients with a creatinine clearance of 30 mL/min or less,

or monitoring of anti-Xa activity if LMWH is used (4, 7).
However, the evidence for this recommendation is conflicting (8) and there are no reliable data to guide the
interpretation of anti-Xa levels to monitor treatment or to
adjust LMWH doses (7). Despite this limitation, anti-Xa
levels are the only available method to monitor LMWH
activity and their use in clinical practice is based on consensus recommendations. Peak anti-Xa levels occur 4 hours
after a therapeutic dose of subcutaneous LMWH is administered. Peak levels above the upper limit of the recommended therapeutic range (0.6 to 1.0 IU/mL) may be associated with an increased risk for bleeding (4).
To further clarify the relationship between LMWH
anti-Xa levels and creatinine clearance and the risk for
bleeding in patients with a creatinine clearance of 30 mL/
min or less, we performed a systematic review of all studies
of LMWH in non dialysis-dependent patients with varying degrees of renal function that reported creatinine clearance and anti-Xa levels or major bleeding events.

METHODS
This study was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE)
guidelines (9).
Study Identification

We attempted to identify all published and unpublished studies of LMWH in non dialysis-dependent patients with renal insufficiency using the MEDLINE (1966
to week 3 of November 2005), EMBASE (1980 to 2005,
week 51), and Cochrane Library (2005, Issue 4) electronic
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Two unmasked investigators independently assessed

study quality according to the following criteria: 1) method
of patient enrollmentstudies with consecutive patient
enrollment were considered to be of higher quality than
those with nonconsecutive enrollment; 2) duration and
completeness of patient follow-up for major bleeding
studies with longer and more thorough follow-up were
considered to be of higher quality because major bleeding
outcomes are more accurately reported; and 3) method of
outcome ascertainmentstudies in which bleeding was
objectively and reproducibly assessed by using a priori definitions were rated higher than those that did not use
bleeding definitions or those that had unclear or nonobjective methods of measurement.
Data Extraction

Two unmasked investigators independently extracted

data on study design, patient characteristics, renal function, type and dose of LMWH, anti-Xa levels, and number
of major bleeding episodes. Data were extracted in duplicate, and disagreements were resolved through discussion.
We defined a creatinine clearance of 30 mL/min or less as
severe renal insufficiency, calculated by using the CockcroftGault (10) or Modification of Diet in Renal Disease
(MDRD) (11) equation. For studies that adopted other
thresholds to define severe renal failure or those that reported only mean creatinine clearance, we contacted the
authors to obtain the data corresponding to a creatinine
clearance threshold of 30 mL/min.
We extracted peak anti-Xa levels 4 hours after subcutaneous injection of LMWH because peak levels correlate
more strongly with efficacy and safety than do trough levels
(12). Because maximum LMWH activity (Amax) is obwww.annals.org

Low-Molecular-Weight Heparin in Renal Insufficiency

served at 4 hours, Amax data were considered equivalent to

4-hour anti-Xa levels. A meta-analysis of anti-Xa levels at 4
hours was not performed because measures of variance
were not reported in most studies, thereby precluding
pooling of the data. We report the anti-Xa data according
to LMWH type because differences in molecular weight
and charge density of LMWH may result in differences in
renal clearance and anti-Xa levels (13, 14). The LMWHs,
such as tinzaparin, that are structurally similar to UFH
may be less prone to accumulate in patients with renal insufficiency than smaller, less negatively charged
LMWHs, such as enoxaparin.
We accepted the definitions of major bleeding reported by authors and did not reclassify events. Therapeutic doses of LMWH (enoxaparin, 1.5 mg/kg of body
weight once daily or 1 mg/kg twice daily; tinzaparin, 175
IU/kg once daily; dalteparin, 200 IU/kg once daily or 100
IU/kg twice daily) and prophylactic doses (enoxaparin, 40
mg once daily or 30 mg twice daily) were defined according to the product monographs. Adjusted-dose LMWH
was defined as any dose that was modified empirically or
according to renal function or measured anti-Xa levels.
If the required data could not be extracted from the
published report, we contacted the corresponding author
by e-mail to request additional data. If a response was not
received after 15 days, we sent a second e-mail; if we still
received no response, we contacted secondary authors.
Statistical Analysis

To assess the agreement between reviewers for study

selection, we used the k statistic, which measures chancecorrected agreement (15). The odds ratio for major bleeding in patients with and without severe renal insufficiency
treated with LMWH was calculated for each study and
pooled with the Peto method (fixed-effects) by using Review Manager, version 4.2 (RevMan, Oxford, United
Kingdom; the Cochrane Collaboration, 2003). Statistical
heterogeneity was evaluated by using the I2 statistic, which
measures the extent of inconsistency among study results
and describes the proportion of total variation in study
estimates that is due to heterogeneity rather than sampling
error. We preferred the Peto method to other statistical
approaches for combining odds ratios because it provides
relatively unbiased estimates of treatment effects when the
event rates are low. We also calculated a pooled risk difference and 95% CIs by using exact statistical methods for
stratified 2 2 tables.
Two a priori secondary analyses were performed. The
first compared major bleeding according to LMWH type
because accumulation may vary among different preparations in patients with renal insufficiency (13, 14). The
second compared major bleeding according to LMWH
dose. Because bleeding is correlated with the intensity of
anticoagulation, studies using therapeutic doses reported
higher bleeding rates than those using prophylactic doses.
A sensitivity analysis that included only high-quality
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Review

studies was performed to assess the robustness of our primary results. A funnel plot of effect size versus standard
error was used to assess possible publication bias (16).
Role of the Funding Source

No funding was received for this study.

RESULTS
Study Identification and Selection

Our search identified 875 published studies (219 from

MEDLINE, 792 from EMBASE, and 24 from the
Cochrane Library); 141 studies were duplicated in the 3
databases (Figure 1). Contact with experts did not reveal
additional published or unpublished studies. We excluded
839 studies after screening their titles and abstracts and
retrieved the remaining 36 studies for more detailed evaluation (1752). Of the 36 retrieved studies, 19 were excluded: 3 contained duplicate data (21, 32, 42); 2 did not
include patients with a creatinine clearance of 30 mL/min
or less (25, 44); 1 only included patients with a creatinine
clearance of 30 mL/min or less (20); 3 involved hemodialysisdependent patients (23, 41, 48); 1 used a noncommercially
available LMWH (47); 3 administered LMWHs intravenously (35, 46, 52); 3 used therapeutic- and prophylacticdose LMWH and separate data for the 2 groups could not
be obtained (33, 40, 43); 2 examined LMWH population
pharmacokinetics but data for patients with severe renal
insufficiency could not be obtained (22, 51); and 1 registry
used different LMWH preparations and data specific for
LMWH type could not be obtained (50). One additional
study was identified through manual review of references
(53). Thus, 18 studies were included in the systematic review (1719, 24, 26 31, 34, 36 39, 45, 49, 53), 13 that
reported anti-Xa levels (17, 19, 26, 30, 31, 34, 36 39, 45,
49, 53) and 12 that compared the rate of major bleeding in
patients with and without renal insufficiency (1719, 24,
26 30, 36, 39, 53). The interobserver agreement for study
selection was excellent (k 0.98).
Study Characteristics

All studies were published in English and included 18

to 3501 patients (Table 1). Two studies reported results
from subgroups of patients enrolled in randomized trials of
enoxaparin for acute coronary syndromes (29, 37), 12 were
prospective cohort studies (17, 18, 26, 30, 31, 34, 36, 38,
39, 45, 49, 53), and 4 were retrospective cohort studies
(19, 24, 27, 28).
Creatinine clearance was calculated by using the CockcroftGault equation in 12 studies (1719, 24, 26, 28, 29,
34, 36, 37, 49, 53) and by using the Modification of Diet
in Renal Disease (MDRD) equation in 2 studies (27, 30).
One study measured endogenous creatinine clearance (38),
1 used the KampmannSiersbaek-Nielsen equation (45),
and 2 did not specify the method of calculation (31, 39).
The indications for LMWH treatment included acute
coronary syndromes, atrial fibrillation, venous thromboem2 May 2006 Annals of Internal Medicine Volume 144 Number 9 675

Review

Low-Molecular-Weight Heparin in Renal Insufficiency

Figure 1. Study selection progression.

ministered multiple doses. All studies measuring anti-Xa

levels used chromogenic anti-Xa assays.
Study Quality

Consecutive patients were enrolled in 12 of the 14

prospective studies; enrollment was nonconsecutive in the
2 pharmacokinetic studies (38, 45). Mean duration of follow-up for bleeding events ranged from 5 to 45 days, and
most studies followed patients during their hospital stay
but did not report the actual duration of follow-up. Follow-up was not evaluable for retrospective studies or those
measuring anti-Xa levels only. Major bleeding was defined
a priori in 10 of the 12 studies that reported bleeding
outcomes (17, 19, 24, 2730, 36, 39, 53); 2 of these studies adapted the Thrombolysis in Myocardial Infarction
(TIMI) criteria for bleeding (19, 39), 1 used a modified
version of the Warfarin Optimized Outpatient Follow-up
Study Classification (17), and 7 defined major bleeding
using 1 or more of the following criteria: decrease in hemoglobin level, transfusion requirements, bleeding into a
critical organ, or death. None of the prospective studies
reported the frequency of bleeding assessments.
Measured Outcomes
Anti-Xa Measurements

LMWH low-molecular-weight heparin.

bolism, and prevention of thromboembolic complications

in patients with prosthetic heart valves. Two pharmacokinetic studies evaluated LMWH in healthy persons or in
patients with renal insufficiency (38, 45).
Fifteen studies used enoxaparin (1719, 24, 26 31,
34, 3739, 45), 2 used tinzaparin (36, 53), and 1 used
dalteparin (49). Of the 15 enoxaparin studies, 7 used therapeutic doses, 4 used empirically adjusted doses, 3 used
prophylactic doses, and 1 used both therapeutic and prophylactic doses. The 2 tinzaparin studies and the dalteparin
study used therapeutic doses. Fourteen of the 16 enoxaparin studies and the tinzaparin and dalteparin studies ad676 2 May 2006 Annals of Internal Medicine Volume 144 Number 9

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Enoxaparin. Ten enoxaparin studies measured anti-Xa

levels: 4 therapeutic-dose studies (17, 26, 30, 37), 3 adjusted-dose studies (19, 31, 39), and 3 prophylactic-dose studies (34, 38, 45) (Table 2). For the 4 therapeutic-dose studies using 1 mg/kg every 12 hours, mean anti-Xa levels after
a minimum of 3 doses ranged from 1.27 to 1.58 IU/mL in
patients with a creatinine clearance of 30 mL/min or less
and 0.91 to 1.06 IU/mL in patients with a creatinine clearance greater than 30 mL/min. In 3 of the 4 studies, levels
of anti-Xa were statistically significantly higher among patients with a creatinine clearance of 30 mL/min or less (26,
30, 37).
Three studies evaluated empirically adjusted doses of
enoxaparin. In 2 studies, patients with a creatinine clearance of 30 mL/min or less received 65% of the recommended enoxaparin dose of 1 mg/kg every 12 hours for the
first 3 doses; subsequent doses were adjusted according to
the peak anti-Xa level measured 4 hours after the third
injection, aiming for a target anti-Xa level of 1.0 IU/mL
(31, 39). One of these studies compared the peak anti-Xa
level in patients with and without renal insufficiency and
found no statistically significant difference (31). In the
third study, all patients received an initial dose of 1 mg/kg,
but patients with a creatinine clearance of 30 mL/min or
less subsequently received 0.5 mg/kg and those with a creatinine clearance of 30 to 60 mL/min received 0.75 mg/kg,
both administered every 12 hours (19). The resulting antiXa levels remained within the predefined therapeutic target levels of anti-Xa specified by the authors (0.60 to
1.00 IU/mL); the mean anti-Xa level was 0.65 IU/mL
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Low-Molecular-Weight Heparin in Renal Insufficiency

Review

Table 1. Study and Patient Characteristics*

Study Design
and Method of
Enrollment

Funding
Source

Indication for
LMWH

Creatinine Patients, Mean Dose

Clearance, n
mL/min

Prospective
cohort; C

Industry

ACS, AF, VTE

Macie et al.,
2004 (24)
Peng et al.,
2004 (26)

Retrospective
cohort
Prospective
cohort; C

Not funded

ACS

Thorevska et al.,
2004 (27)
Spinler et al.,
2003 (29)

Retrospective
NS
cohort
Randomized,
Industry
controlled trial
subgroup; C

ACS, AF, VTE,

other
ACS

1030
3150
50
25
25
30
3160
60
30
30
30
30

36
54
106
7
201
7
19
24
65
171
69
3432

Chow et al.,
2003 (30)

Prospective
cohort; C

NS

ACS, AF, VTE,

stroke

Khazan et al.,
2003 (28)

Retrospective
cohort

Hospital

AF

10
1130
3160
60
30
30

1
4
6
7
17
61

Becker et al.,
2002 (37)

Randomized,
Industry
controlled trial
subgroup;
C; NS

ACS

40
4080
80

11
149
273

Retrospective
cohort

NS

AF

30
30

36
47

30 mg every 12 h or
40 mg/d

Prospective
cohort; C
Prospective
cohort; NC

NS

VTE prophylaxis
PK study in
volunteers

Prospective
cohort; NC

Industry

PK study in
volunteers

4
64
12
12
12
12
12
12

4000 IU (40 mg) daily

Industry

40
40
30
3150
5180
80
20
Normal

Prospective
cohort; C

Industry

ACS

30
3050
5180
80

18
11
6
3

Retrospective
cohort

NS

ACS, AF, VTE,

other

30

50

Study, Year
(Reference)
Enoxaparin
Therapeutic dose
Bazinet et al.,
2005 (17)

Prophylactic dose
Khazan et al.,
2003 (28)
Mahe et al.,
2002 (34)
Sanderink et al.,
2002 (38)

Cadroy et al.,
1991 (45)
Adjusted dose
Green et al.,
2005 (18)

Kruse and Lee,

2004 (19)

Professional
ACS, AF, VTE,
organization
prosthetic valves

3060

120

1 mg/kg every 12 h
or 1.5 mg/kg per d
1 mg/kg every 12 h
1 mg/kg every 12 h

1 mg/kg every 12 h
30 mg IV loading dose,
then 1 mg/kg every
12 h
1 mg/kg every 12 h

1 mg/kg every 12 h
or 1.5 mg/kg per d
30 mg IV loading dose,
then 1 mg/kg every
12 h or 1.25 mg/kg
every 12 h

40 mg/d

0.5 mg/kg single dose

Creatinine clearance
25 mL/min: 0.75
mg/kg every 12 h;
creatinine clearance
25 mL/min: 1
mg/kg every 12 h
1 mg/kg every 12 h
(initial dose), then 0.5
mg/kg every 12 h
0.75 mg/kg every
12 h
Not specified

Major
Bleeding,
%

1 (2.8)
2 (3.7)
0
2 (28.6)
6 (3.0)
0

7 (10.8)
11 (6.4)
5 (7.5)
74 (1.1)

0
0
0
0
2 (11.8)
3 (4.9)
Unable to
obtain

3 (8.3)
3 (6.4)
Not
assessed
Not
assessed

Not
assessed

Prospective
cohort; C

NS

ACS

30
3060
60

28
28
55

0.64 (SD, 0.04) mg/kg

every 12 h, 0.84 (SD,
0.03) mg/kg every 12
h, 0.92 (SD, 0.03)
mg/kg every 12 h

0
1 (3.6)
0

Prospective
cohort; C

Not funded

ACS, AF, VTE,

other

2034
3549
5064
65

51
60
44
45

175 IU/kg daily

0
1 (1.7)
0
2 (4.4)

Collet et al.,
2001 (39)

Tinzaparin
Pautas et al.,
2002 (36)

0.70 (SD, 0.07) mg/kg

every 12 h

1 (0.8)

62
453

Prospective
cohort; C

While receiving
enoxaparin
(NS); NA

In-hospital (NS); NA

30
30

Collet et al.,
2003 (31)

AF

While receiving
enoxaparin
(NS); NA
14 d; NS

Professional
ACS
organization

NS

ESSENCE: 30 d,
TIMI 11B: 72 h,
in-hospital and day
43; NS
In-hospital (NS);
no loss to
follow-up

NS

10
42

Retrospective
cohort

5 d;
92% follow-up
for anti-Xa
In-hospital (10 d);
NA
In-hospital (NS);
no loss to
follow-up
In-hospital (NS); NA

1 (5.6)
0
0
0

30
30

Khazan et al.,
2003 (28)

Bleeding Follow-up:
Mean Duration;
Completeness

0
3 (7.1)
Unable to
obtain

While receiving
enoxaparin
(NS); NA
30 d; NS (88.5%
follow-up for
ischemic events)
In-hospital (NS); no
loss to follow-up

30 d; no loss to
follow-up

Continued on following page

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Low-Molecular-Weight Heparin in Renal Insufficiency

Table 1Continued
Study, Year
(Reference)
Siguret et al.,
2000 (53)

Study Design
and Method of
Enrollment

Funding
Source

Indication for
LMWH

Creatinine
Clearance,
mL/min

Prospective
cohort; C

NS

AF, VTE, other

2029
3039
4049
50

NS

ACS, AF, VTE

40
80

Dalteparin
Shprecher et
Prospective
al., 2005 (49)
cohort; C

Patients,
n
8
9
6
7

11
11

Mean Dose

175 IU/kg per d

100 IU/kg every 12 h

Major
Bleeding,
%
0
0
0
0

Not
assessed

Bleeding Follow-up:
Mean Duration;
Completeness
10 d; no loss to
follow-up

* ACS acute coronary syndrome; AF atrial fibrillation; ESSENCE Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events; IV
intravenous; LMWH low-molecular-weight heparin; NA not applicable; NC nonconsecutive (not applicable to retrospective cohorts); NS not specified; PK
pharmacokinetic; TIMI Thrombolysis in Myocardial Infarction; VTE venous thromboembolism.
Creatinine clearance calculated by CockcroftGault equation except in Thorveska et al. (27) and Chow et al. (30) (Modification of Diet in Renal Disease equation),
Sanderink et al. (38) (endogenous creatinine clearance), and Cadroy et al. (45) (Kampmann equation).
Bleeding assessed using TIMI criteria for bleeding from references 19, 29, and 31.
Completeness of follow-up not applicable to retrospective studies and studies that assessed anti-Xa only.

(mean, 0.19) for patients with a creatinine clearance of 30

mL/min or less and 0.82 IU/mL (mean, 0.18) for patients
with a creatinine clearance of 30 to 60 mL/min (P
0.001).
Two of the prophylactic-dose studies evaluated multiple doses using the recommended dose of 40 mg daily (54),
and 1 evaluated a single dose of 0.5 mg/kg. With the
40-mg dose, 1 study showed no difference in the mean
4-hour anti-Xa level in patients with a creatinine clearance
less than 40 mL/min versus those with a creatinine clearance of 40 mL/min or greater (34); a pharmacokinetic
study found that mean anti-Xa levels were almost 40%
higher in patients with a creatinine clearance of 30 mL/
min or less versus those with a creatinine clearance greater
than 30 mL/min (38). A single dose of 0.5 mg/kg resulted
in higher levels of anti-Xa in patients with a creatinine
clearance of 20 mL/min or less than in those with normal
renal function (creatinine clearance 85 mL/min) (45).
However, in each study, peak levels of anti-Xa remained
below the lower limit of the usual target therapeutic range
for LMWH.
Tinzaparin. Two therapeutic-dose studies evaluated
levels of anti-Xa in elderly patients with impaired renal
function (36, 53). These studies did not find a correlation
between the peak level of anti-Xa and creatinine clearance,
but comparison of levels of anti-Xa between patient groups
was not reported.
Dalteparin. In a single study evaluating therapeuticdose dalteparin, comparison of the mean 4-hour anti-Xa
levels in patients with a creatinine clearance of 40 mL/min
or less versus normal renal function showed no difference
between the groups (49).
Bleeding Events

Major bleeding events in patients with and without

severe renal insufficiency were reported in 12 studies involving 4971 patients. Ten studies involving 4741 patients
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used enoxaparin (1719, 24, 26 30, 39), and 2 studies

involving 230 patients used tinzaparin (36, 53). Use of
LMWH in patients with a creatinine clearance of 30 mL/
min or less versus those with a creatinine clearance greater
than 30 mL/min was associated with an increased risk for
major bleeding (5.0% vs. 2.4%; odds ratio, 2.25 [CI, 1.19
to 4.27]; P 0.013) (Figure 2). There was evidence of
statistical heterogeneity (I2 50.4%; P 0.028).
For the secondary analysis according to LMWH type,
use of enoxaparin in patients with severe renal insufficiency
increased the rate of major bleeding (6.0% vs. 2.4%; odds
ratio, 2.59 [CI, 1.34 to 5.01]) (Figure 3). The data for
bleeding events were not pooled in the 2 tinzaparin studies
because the odds ratios for bleeding could not be calculated
for 1 study that had no bleeding events. We also could not
pool these data for the prophylactic-dose studies because
they were available for only 1 study (28). Among therapeutic-dose enoxaparin studies, major bleeding was statistically
significantly higher among patients with a creatinine clearance of 30 mL/min or less versus those with a creatinine
clearance greater than 30 mL/min (8.3% vs. 2.4%; odds
ratio, 3.88 [CI, 1.78 to 8.45]). When enoxaparin doses
were adjusted empirically according to creatinine clearance
or measured anti-Xa levels, the odds ratio for major bleeding was lower, although the CIs were broad (0.9% vs.
1.9%; odds ratio, 0.58 [CI, 0.09 to 3.78]).
In the sensitivity analysis, all prospective studies reported consecutive patient enrollment and follow-up for
major bleeding was reported as in hospital for almost all
studies; therefore, we could not separate studies by quality
on the basis of these 2 characteristics. The sensitivity analysis was thus based on the use of bleeding definitions defined a priori. After the 2 studies that did not state definitions a priori (18, 26) were excluded, the odds ratio for
major bleeding in patients with severe renal insufficiency
receiving LMWH was 2.17 (CI, 1.14 to 4.16).
Results obtained by using exact statistical methods for
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Low-Molecular-Weight Heparin in Renal Insufficiency

Review

Table 2. Measured Anti-Xa Levels and Relation to Renal Function*

Study, Year
(Reference)
Enoxaparin
Therapeutic dose
Bazinet et al.,
2005 (17)

Peng et al.,
2004 (26)

Chow et al.,
2003 (30)

Becker et al.,
2002 (37)

Dose

Timing of Anti-Xa
Measurement

Creatinine
Clearance,
mL/min

Anti-Xa Level and Dosing

Schedule, IU/mL

Conclusions

1 mg/kg every
12 h or 1.5
mg/kg per d

After 2nd or 3rd

dose, based on a
daily dosing
schedule; after
4th or 5th dose,
based on a
twice-daily dosing
schedule
After 3rd dose
(mean, 5.2 doses)

1030

1.18 (daily dosing);

1.27 (twice-daily dosing)

3150

1.21 (daily dosing);

1.25 (twice daily dosing)

Anti-Xa decreases with higher creatinine

clearance (0.003 IU/mL for each mL/min);
twice-daily dosing can result in
supratherapeutic anti-Xa levels in patients
with creatinine clearance 30 mL/min

50

1.10 (daily dosing);

1.06 (twice-daily dosing)

1 mg/kg every
12 h

1 mg/kg every
12 h

1 mg/kg or 1.25
mg/kg every
12 h

After 3rd dose

After 3rd or 5th

dose, timing not
specified

30

1.58 (SD, 0.54)

3160

1.25 (SD, 0.38)

60

0.93 (SD, 0.28)

30

1.34

30

0.91

40

1.58 (3rd dose); 1.53

(5th dose)
1.41 (3rd dose);
1.53 (5th dose)
1.25 (3rd dose); 1.29
(5th dose)

4080
80

Adjusted dose
Kruse and Lee,
2004 (19)

30

0.65 (SD, 0.19)

3060

0.82 (SD, 0.18)

After 3rd dose

30

0.85 (SD, 0.05)

30

0.95 (SD, 0.02)

Before cardiac
catheterization
(mean, 5.4 h [SD,
0.2] after 3.9 d
[SD, 0.4])

0.95 (SD, 0.07)

3160

0.95 (SD, 0.05)

60

1.01 (SD, 0.05)

After 1st or 2nd

dose
After 1st and 4th
dose

40
40
30

0.49
0.52
0.46 (day 1); 0.58 (day 4)

3150

0.45 (day 1); 0.50 (day 4)

5180

0.49 (day 1); 0.56 (day 4)

80

0.39 (day 1); 0.42 (day 4)

20

Mean, 0.35 (SD, 0.07)

85

Mean, 0.29 (SD, 0.06)

2034

0.69 (day 2); 0.87 (day 10);

0.83 (day 20); 0.90 (day 28)
0.81 (day 2); 0.85 (day 10);
0.82 (day 20); 0.84 (day 28)
0.81 (day 2); 0.85 (day 10);
0.81 (day 20); 0.78 (day 28)
0.83 (day 2); 0.84 (day 10);
0.89 (day 20); 1.09 (day 28)

1 mg/kg, then
0.5 or 0.75
mg/kg every
12 h

After 3rd dose

Collet et al.,
2003 (31)

1 mg/kg, then
65% of dose

Collet et al.,
2001 (39)

1 mg/kg, then
65% of dose

Prophylactic dose
Mahe et al.,
2002 (34)
Sanderink et al.,
2002 (38)

Cadroy et al.,
1991 (45)

Tinzaparin
Pautas et al.,
2002 (36)

4000 IU/d
40 mg/d

0.5 mg/kg
(single dose)

175 IU/kg per d

After single dose

5 h after the 1st

dose and once
weekly

3549
5064
65

Significantly higher peak anti-Xa levels are

found in patients with renal insufficiency;
dose adjustment and/or laboratory
monitoring is recommended with creatinine
clearance 30 mL/min
Inverse correlation between creatinine
clearance and peak anti-Xa levels; dose
adjustments recommended for creatinine
clearance 30 mL/min
In patients with creatinine clearance 30
mL/min compared with those with normal
renal function, 1) clearance reduced by
22%; 2) higher trough and peak anti-Xa
activity; 3) dose adjustment necessary

Adjusted dose produces therapeutic-range

anticoagulation with bleeding incidence
similar to normal renal function
New dose current dose goal anti-Xa/
current anti-Xa
Adjusted dose provides adequate anti-Xa levels
and no excess of bleeding in patients with
creatinine clearance 30 mL/min
Adjusted dose results in a safe level of
anticoagulation

No correlation between anti-Xa activity and

creatinine clearance
In patients with creatinine clearance 30
mL/min compared with those with normal
renal function, 1) elimination decreased by
35% and more evident with repeated
dosing; 2) increased anti-Xa exposure caused
by a slower rate of elimination, not by
differences in absorption; 3) may need dose
adjustment
Decreased elimination in patients with
creatinine clearance 20 mL/min compared
with healthy persons (higher Amax, longer
Tmax, increased area under the
receiver-operating curve, reduced clearance,
and longer elimination of half-life)

No correlation between anti-Xa activity and

creatinine clearance or age for each group

Continued on following page

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2 May 2006 Annals of Internal Medicine Volume 144 Number 9 679

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Low-Molecular-Weight Heparin in Renal Insufficiency

Table 2Continued
Study, Year
(Reference)
Siguret et al.,
2000 (53)

Dose

Timing of Anti-Xa
Measurement

Creatinine
Clearance,
mL/min

Anti-Xa Level and Dosing

Schedule, IU/mL

Conclusions

175 IU/kg per d

5 h after 2nd and

10th dose

2029

0.73 (SD, 0.16) (day 2);

0.77 (SD, 0.19) (day 10)
0.57 (SD, 0.26) (day 2);
0.60 (SD, 0.21) (day 10)
0.72 (SD, 0.22) (day 2);
0.75 (SD, 0.19) (day 10)
0.65 (SD, 0.14) (day 2);
0.71 (SD, 0.19) (day 10)

No correlation between anti-Xa activity and

creatinine clearance and no accumulation of
anti-Xa activity

Mean, 0.47 (SD, 0.25)

Mean, 0.55 (SD, 0.20)

No difference in anti-Xa activity between

groups

3039
4049
50

Dalteparin
Schprecher et al.,
2005 (45)

100 IU/kg every

12 h

3 to 5 h after 5th
or 6th dose

40
80

* Anti-Xa measurement at 4 hours after injection, unless indicated. Amax maximum low-molecular-weight heparin activity; Tmax time of maximum observed activity.
Creatinine clearance calculated by CockcroftGault equation except in Chow et al. (30) (Modification of Diet in Renal Disease equation), Sanderink et al. (38)
(endogenous creatinine clearance), and Schprecher et al. (45) (Kampmann equation).
Doses calculated as follows: creatinine clearance 30 mL/min received 65% of recommended dose, anti-Xa measured 4 hours after the 3rd injection, and enoxaparin dose
adjusted aiming for anti-Xa levels of 0.5 to 1.0 IU/mL.

stratified 2 2 tables to calculate a pooled risk difference

were consistent with those obtained by calculating the Peto
odds ratios and therefore yielded similar conclusions (results not presented).
Assessment of Publication Bias

A funnel plot of relative risk versus standard error included 9 of the 12 studies (1719, 24, 2729, 36, 39)
because no bleeding events occurred in 3 studies. The funnel plot was asymmetrical, with an absence of studies in the
bottom right-hand corner (data not shown).

DISCUSSION
Our results show that when standard therapeutic-dose
LMWH (enoxaparin) is used in patients with severe renal
insufficiency (creatinine clearance 30 mL/min) compared with those without (creatinine clearance 30 mL/
min), anti-Xa levels are higher and the risk for major bleeding events is increased 2- to 3-fold. Because almost all
included studies used enoxaparin, these data suggest that
standard, weight-adjusted, therapeutic-dose, unmonitored
enoxaparin should be avoided in patients with severe renal
insufficiency. There are insufficient data to make conclusions regarding tinzaparin, dalteparin, or other LMWH
preparations.
In patients with unstable angina and nonST-segment
elevation myocardial infarction, suboptimal anticoagulation with LMWH (anti-Xa level 0.5 IU/mL) is associated with an increased risk for recurrent ischemic events
and is an independent predictor of mortality (21). Our
results suggest that when the enoxaparin dose in patients
with acute coronary syndromes and severe renal insufficiency is adjusted, either empirically or on the basis of
anti-Xa heparin levels, therapeutic anti-Xa levels can be
achieved and excessive levels can be avoided. However, the
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odds ratio for adjusted-dose enoxaparin was associated with

wide CIs; therefore, we cannot definitely conclude that
empirically dose-adjusted enoxaparin is not associated with
increased risks for major bleeding events. This strategy
merits further evaluation, both in patients with acute coronary syndromes and in those with venous thromboembolism who have severe renal insufficiency.
Analysis by study quality did not affect the results.
Although the method of patient enrollment and duration
of follow-up were similar in all studies, the sensitivity analysis, which included only studies using a priori bleeding
definitions, resulted in a similar 2- to 3-fold increase in
major bleeding when LMWH was used in patients with
severe renal insufficiency.
The data for tinzaparin in patients with severe renal
insufficiency are limited. There was no correlation between
creatinine clearance and anti-Xa levels and no statistically
significant increase in anti-Xa levels after 10 days of therapeutic-dose tinzaparin in elderly patients with a mean creatinine clearance of 41 mL/min, but anti-Xa levels were
not compared between patients with and without renal
insufficiency (36, 53). The data for dalteparin also were
limited. Although there was no difference in the mean
anti-Xa levels in patients with and without renal insufficiency, this was based on the mean of 1 measurement in
only a small number of patients (49).
We cannot make definitive conclusions concerning the
appropriate threshold below which clinicians should be
concerned about the risk for LMWH accumulation. Population pharmacokinetic analyses using anti-Xa levels (32,
40) followed by simulations to determine a dosing strategy
have been published (18, 51). However, these strategies
have not been evaluated in patients with renal insufficiency. The risk for excessive levels of anti-Xa is higher
when therapeutic doses are used, but multiple prophylactic
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Low-Molecular-Weight Heparin in Renal Insufficiency

Review

Figure 2. Peto odds ratio (OR) of major bleeding events in patients with severe renal insufficiency (creatinine clearance <30
mL/min) compared with patients without renal insufficiency (creatinine clearance >30 mL/min).

doses are still associated with LMWH accumulation, and

laboratory monitoring or dose reduction may also be necessary in patients with severe renal insufficiency. This is
particularly relevant for patients who require long-term
prophylactic-dose LMWH therapy.
There were considerable differences among the studies
included in our review, including age, concomitant antiplatelet therapy (in the studies evaluating enoxaparin for
acute coronary syndromes), number of doses of LMWH
administered, and frequency of bleeding outcome assessment, all of which affect the risk for bleeding. Furthermore, differences in the methods used to calculate creatinine clearance may have affected the proportion of patients
defined as having severe renal insufficiency. Finally, although all studies used chromogenic anti-Xa assays, different assays and instruments can produce different anti-Xa
results (55).
In the Global Registry of Acute Coronary Events
(GRACE) study (50), major bleeding events during
LMWH therapy occurred in 5.90% of patients with severe
renal insufficiency (creatinine clearance 30 mL/min), in
2.03% of patients with moderate renal insufficiency (creatinine clearance 30 to 60 mL/min), and in 1.24% of pawww.annals.org

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tients with normal renal function (creatinine clearance

60 mL/min). This study did not meet our inclusion criteria because various LMWH preparations and doses were
used. However, a pooled analysis including these data did
not alter our results or conclusions: Major bleeding occurred in 5.4% of patients with a creatinine clearance of 30
mL/min or less compared with 2.0% of patients with a
creatinine clearance greater than 30 mL/min (odds ratio,
3.85 [CI, 2.29 to 6.48]; P 0.001).
Our study has several potential limitations. First, although most studies enrolled consecutive patients, the potential for confounding by indication cannot be excluded.
For example, patients at lower risk for bleeding events may
have been preferentially included, which may lead to an
underestimate of the risk for these events associated with
LMWH in patients with severe renal insufficiency (9). To
minimize potential biases, we excluded case reports and
selected studies with 10 or more patients. Second, relatively few patients with severe renal insufficiency were included in our analyses, and the number of bleeding events
was modest. Third, despite careful electronic and manual
searches and contact with content experts to identify all
available data, the funnel plot of study size versus treat2 May 2006 Annals of Internal Medicine Volume 144 Number 9 681

Review

Low-Molecular-Weight Heparin in Renal Insufficiency

Figure 3. Peto odds ratio (OR) of major bleeding events with enoxaparin in patients with severe renal insufficiency (creatinine
clearance <30 mL/min) compared with patients without renal insufficiency (creatinine clearance >30 mL/min).

ment effect was asymmetrical, which suggests publication

bias attributable to underreporting of small studies showing an increased risk for major bleeding events. However,
this probably underestimates rather than overestimates ma682 2 May 2006 Annals of Internal Medicine Volume 144 Number 9

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jor bleeding events when LMWH is used in patients with

severe renal insufficiency. Fourth, although the point estimate for major bleeding events when adjusted-dose enoxaparin is used in patients with severe renal insufficiency
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Low-Molecular-Weight Heparin in Renal Insufficiency

suggests that this strategy is not associated with increased

risks, there may still be a clinically important increase in
risk because lack of evidence of a difference is not the same
as evidence of no difference. Furthermore, the comparison
between standard-dose and adjusted-dose enoxaparin was
not randomized. Finally, although our review included 3
LMWHs, most of the available data were for enoxaparin;
data for tinzaparin and dalteparin are limited, precluding
definitive conclusions regarding the use of these and other
LMWHs in patients with severe renal insufficiency.
Our findings have important clinical implications.
Enoxaparin is widely used in patients with acute coronary
syndromes and acute venous thromboembolism. Approximately 50% of these patients have impaired renal function,
and a substantial minority have severe renal insufficiency
(50, 56, 57). Our results suggest that renal function should
be measured in all patients requiring therapeutic-dose
LMWH and that the dose should be reduced or the anti-Xa level should be monitored in patients with a creatinine clearance of 30 mL/min or less. Prophylactic-dose
LMWH should also be used with caution in patients with
severe renal insufficiency, and empirical dose reduction
may be prudent.
Future studies should examine the pharmacokinetic
profiles of different LMWHs in patients with varying degrees of renal insufficiency to better assess the risk for accumulation and bleeding events during extended treatment
with prophylactic and therapeutic doses of LMWH. Randomized trials are needed to compare different doses of
LMWH in patients with varying degrees of renal insufficiency to determine the optimal anticoagulant strategy that
minimizes the risk for bleeding complications while maintaining antithrombotic efficacy.
In conclusion, standard, weight-adjusted LMWH
(enoxaparin) is associated with a 2- to 3-fold increased risk
for major bleeding events in patients with severe renal insufficiency (creatinine clearance 30 mL/min) versus patients without renal insufficiency. Adjusted doses of
LMWH may reduce the risk for bleeding events in these
patients but needs to be further evaluated.
From McMaster University and Hamilton General Hospital, Hamilton,
Ontario, Canada, and University of Insubria, Varese, Italy.
Acknowledgments: The authors thank Dr. Qilong Li for providing

additional statistical analyses and the authors of the primary studies, Drs.
L. Lalonde, I. Mahe, V. Siguret, and N. Thorevska, who kindly provided
information included in the meta-analysis.
Grant Support: Dr. Crowther is a Career Investigator of the Heart and
Stroke Foundation of Canada; Dr. Eikelboom holds a Tier II Canada
Research Chair in Cardiovascular Medicine from the Canadian Institutes
for Health Research; and Dr. Lim is the recipient of a Graduate Scholarship from the Canadian Institutes of Health Research.
Potential Financial Conflicts of Interest: Consultancies: M.A. Crowther

(AstraZeneca, Pfizer/Pharmacia, Sanofi-Aventis, GlaxoSmithKline, La

Jolla Pharmaceutical Corporation, Leo Laboratories, Sandoz); Honoraria:
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Review

J.W. Eikelboom (Pharmacia Corp., Sanofi, Aventis), M.A. Crowther

(Pfizer/Pharmacia, Sanofi-Aventis, GlaxoSmithKline, Leo Laboratories,
Calea, Novo Nordisk); Grants received: W. Lim (Sanofi-Aventis), J.W.
Eikelboom (Sanofi, Aventis), M.A. Crowther (Pfizer/Pharmacia, SanofiAventis, Leo Laboratories).
Corresponding Author: Wendy Lim, MD, BSc, St. Josephs Hospital,

50 Charlton Avenue East, Room L208, Hamilton, Ontario L8N 4A6,

Canada; e-mail, limwp@mcmaster.ca.
Current author addresses are available at www.annals.org.

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Annals of Internal Medicine

Current Author Addresses: Drs. Lim and Crowther: St. Josephs Hos-

pital, 50 Charlton Avenue East, Room L208, Hamilton, Ontario L8N

4A6, Canada.
Dr. Dentali: Department of Medicine, University of Insubria, Viale
Borri 57, 21100 Varese, Italy.
Dr. Eikelboom: Hamilton Health Sciences, Hamilton General Hospital,
237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

APPENDIX: MEDLINE SEARCH STRATEGY

Database: Ovid MEDLINE(R) 1966 to November Week
3 2005
Search Strategy:
1. low molecular weight heparin.mp. or exp Heparin, LowMolecular-Weight/ (6850)
2. dalteparin$.mp. or exp Tedelparin/ (653)
3. (tedelparin$ or fragmin$ or kabi2165 or kabi 2165 or
k2165 or k 2165 or fr860 or fr 860).mp. [mp title, original
title, abstract, name of substance word, subject heading word]
(729)
4. enoxaparin$.mp. or exp ENOXAPARIN/ (1604)
5. (lovenox or clexane or klexane or pk10169 or pk 10169
or emt996 or emt 996 or emt967 or emt 967).mp. [mptitle,
original title, abstract, name of substance word, subject heading
word] (155)
6. nadroparin$.mp. or exp NADROPARIN/ (360)
7. (fraxiparin$ or seleparin$ or tedegliparin$ or cy216 or cy
216).mp. [mptitle, original title, abstract, name of substance
word, subject heading word] (268)
8. tinzaparin$.mp. (160)
9. (innohep or logiparin$).mp. [mp title, original title,
abstract, name of substance word, subject heading word] (50)
10. antixarin.mp. (1)
11. (ardeparin$ or normiflo or rd11885 or rd 11885).mp.

W-158 2 May 2006 Annals of Internal Medicine Volume 144 Number 9

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[mptitle, original title, abstract, name of substance word, subject heading word] (33)
12. (bemiparin$ or hibor or ivor or zibor or badyket).mp.
[mptitle, original title, abstract, name of substance word, subject heading word] (128)
13. (certoparin$ or alpharin$ or sandoparin$ or troparin$ or
embolex or monoembolex).mp. [mp title, original title, abstract, name of substance word, subject heading word] (69)
14. (parnaparin$ or fluxum or op2123 or op 2123 or minidalton or alphaLMWH or alpha LMWH).mp. [mptitle, original title, abstract, name of substance word, subject heading
word] (27)
15. (reviparin$ or lu473111 or lu 473111 or clivarin$).mp.
[mptitle, original title, abstract, name of substance word, subject heading word] (109)
16. or/1-15 (7229)
17. kidney failure.mp. or exp Kidney Failure/ (78541)
18. (renal failure or renal insufficiency or kidney insufficiency or renal function or kidney function or renal$ or kidney$).mp. [mptitle, original title, abstract, name of substance
word, subject heading word] (568417)
19. glomerular filtration rate.mp. or exp Glomerular Filtration Rate/ (25533)
20. kidney diseases.mp. or exp Kidney Diseases/ (278443)
21. or/17-20 (615811)
22. 16 and 21 (541)
23. limit 22 to humans (482)
24. limit 23 to (case reports or clinical trial or controlled
clinical trial or multicenter study or randomized controlled trial)
(219)
25. from 24 keep 1-219 (219)

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