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European Journal of Clinical Pharmacology

, Volume 71, Issue 8, pp 921–929 | Cite as

A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency

  • Ferdows Atiq
  • Patricia M.L.A. van den Bemt
  • Frank W.G. Leebeek
  • Teun van Gelder
  • Jorie Versmissen
Open Access
Review Article

Abstract

Purpose

Although therapeutic dosages of most low-molecular-weight heparins (LMWHs) are known to accumulate in patients with renal insufficiency, for the lower prophylactic dosages this has not been clearly proven. Nevertheless, dose reduction is often recommended. We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients.

Methods

A comprehensive search was conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics. The search yielded 674 publications. After exclusion by reading the titles, abstracts, and if necessary the full paper, 11 publications remained.

Results

For dalteparin and tinzaparin, no accumulation was observed. Enoxaparin, on the other hand, did lead to accumulation in patients with renal insufficiency, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation. No data were available for nadroparin.

Conclusions

In this systematic review, we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation. However, prophylactic dosages of enoxaparin, bemiparin, and certoparin did show accumulation in patients with a creatinine clearance (CrCl) below 30 ml/min, and therefore, dose reduction is required. The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs.

Keywords

Clinical trials Heparins Pharmacodynamics Heparins Venous thrombosis 

Introduction

Low-molecular-weight heparins (LMWHs) are anticoagulants made by depolymerization of unfractioned heparin (UFH) [1, 2]. In the last decades, LMWHs have largely replaced UFH as anticoagulants, because they are at least equally effective in prevention and treatment of venous thromboembolisms (VTEs) and have many practical advantages, most importantly the possibility of subcutaneous administration without the need of routine laboratory monitoring of the anticoagulant response [3, 4, 5, 6, 7, 8]. Moreover, LMWHs have a more predictable anticoagulant response, longer half-life (allowing once or twice daily administration), and a dose-independent elimination and they cause less heparin-induced thrombocytopenia [1, 2, 9, 10]. There is conflicting evidence whether bleeding complications differ between LMWHs and UFH, although a Cochrane analysis showed that LMWHs reduce the occurrence of major bleedings [8, 11, 12, 13, 14].

The molecular weights of the various LMWHs differ. Tinzaparin has the highest average molecular weight (6500 Da), while certoparin has the lowest average molecular weight (3800 Da) [13]. Pharmacokinetics of different LMWHs vary: they differ in elimination half-life, clearance, and bioavailability [15, 16]. This might be a consequence of the differences in molecular weight. Also with regard to pharmacodynamics, LMWHs vary: anti-Xa/anti-IIa activity ratios range between 1.5 and 2.5 (tinzaparin and certoparin) to 3.6–6.5 (reviparin) [13].

Since LMWHs are mainly excreted by the kidney, they may accumulate in patients with renal insufficiency increasing the risk of bleeding [17, 18, 19]. Due to above-described differences in pharmacokinetics, data on accumulation in renal insufficiency cannot be easily converted from one LMWH to another [2]. For instance, therapeutic dosages of different LMWHs do not all accumulate in patients with renal insufficiency: nadroparin and enoxaparin were found to accumulate, while tinzaparin did not [20, 21, 22, 23, 24, 25, 26]. For LMHWs that accumulate in a therapeutic dosage, dose reduction is often recommended. Also for the lower prophylactic dosages, such dose reductions have been suggested, especially for high prophylactic dosages such as those used in cancer patients or in high-risk surgery [24, 27, 28, 29].

Even in this era of novel oral anticoagulants, LMWHs will stay important for the initial treatment of VTE during the first 5–7 days in patients treated with dabigatran and edoxaban, as well as for prophylaxis of VTE. Especially for patients with severe renal insufficiency in which case the novel oral anticoagulants are contraindicated, it remains important to know whether LMWHs can be prescribed safely.

Therefore, we conducted a systematic review to investigate whether prophylactic dosages of various LMWHs lead to accumulation defined as an increase in anti-Xa activity and whether accumulation depends on molecular weight of the LMWH.

Materials and methods

The meta-analysis was prepared in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [30]. No prespecified formal protocol was registered.

Article search

A comprehensive, systematic literature search has been conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics using synonyms and relevant terms. The search terms as used in Embase, as an example, are shown in a supplemental file. In addition to the search results, we manually searched reference lists of all relevant articles for additional studies.

Inclusion criteria and exclusion criteria (eligibility criteria)

We only included articles in English on prophylactic LMWH treatment, studying at least ten patients (non-pregnant and with no children) with renal impairment. We defined accumulation as an increase in anti-Xa activity after consecutive administration for several days. Therefore, we excluded studies which did not administer LMWH on consecutive days (except for studies in patients receiving renal replacement therapy) and did not measure anti-Xa activity on multiple days while giving LMWH. We excluded case reports, overviews, expert opinions, recommendations, reviews, and replies on articles. Abstracts of unpublished data were not excluded; authors were approached for additional information.

Study selection and data collection

A single reviewer excluded articles that did not meet the eligibility criteria by using the title and abstract. If necessary, the full text was read. If the reviewer could not decide whether to exclude the article, a second reviewer was asked for advice and both met to reach a consensus. Furthermore, a single reviewer collected relevant data from the included articles for the review.

Risk of bias

Risk of bias was evaluated at study level using the Cochrane Risk of Bias assessment tool. The criteria on random sequence generation, allocation, and blinding were disregarded.

Results

Study selection

The search yielded 1387 articles from which 713 were duplicates. Figure 1 shows a flow diagram illustrating literature evaluation.
Fig. 1

Flow diagram illustrating literature evaluation

Characteristics

Table 1 shows the study and patient characteristics. We included 11 articles of which one was on LMWH in continuous venovenous hemofiltration (CVVH) and one on hemodialysis patients. Five studies examined dalteparin accumulation, and five articles examined enoxaparin [31, 32, 33, 34, 35, 36, 37, 40, 41]. For tinzaparin, bemiparin, and certoparin, there was one study for each LMWH [35, 38, 39].
Table 1

Study characteristics of included studies including patient characteristics and outcome measurements

Study

Study design

LMWH

Patients (n)

Groups

Patient characteristics

Follow-up

Outcomes

Rabbat 2005a [31]

Cohort

Dalteparin

5000 IU

19

NA

IC patients with CrCl ≥ 30

12 daysf (IQR 8–24)

Trough (22–23 h postinjection) and peak anti-Xa

Schmid 2009b [32]

Cohort

Dalteparin

<50 kg 2500 IU

50–100 kg 5000 IU

>100 kg 7500 IU

42

n = 18 CrCl ≥ 60

n = 15 CrCl 30–59

n = 9 CrCl < 30

General medical and surgical ward

3 weeks

Peak anti-Xa

Douketis 2008a [33]

Cohort

Dalteparin

5000 IU

138

NA

ICU patients with CrCl < 30 ml/min

9 daysf (IQR 5–15)

Trough (20 h postinjection) and peak anti-Xa

Tincani 2006b [34]

Cohort

Dalteparin

High risk 5000 IU

Low risk 2500 IU

115

n = 9 CrCl 60–89

n = 73 CrCl 30–59

n = 24 CrCl < 30

Elderly patients (>65 years) with acute illness

6 days

Peak anti-Xa

Mahe 2007a [35]

Randomized

Tinzaparin 4500 IU

Enoxaparin 4000 IU

50

n = 27 tinzaparin;

n = 28 enoxaparin

CrCl 20–50 ml/min, >75 years and weight < 65 kg

8 days

C max, AUC, and trough anti-Xa (24 h postinjection)

Mahe 2007a [36]

Cohort

Enoxaparin 4000 IU

125

CrCl 51–80

CrCl 41–50

CrCl 31–40

CrCl 20–30

Elderly patients (>75 years) with acute medical illness

10 days

Peak anti-Xa. Maximum value per patient was used in the analysis

Sanderink 2002c [37]

Cohort

Enoxaparin

4000 IU

48 (12/group)

CrCl > 80 50 < CrCl ≤ 80

30 < CrCl ≤ 5

CrCl ≤ 30

18–75 years old. BMI 18–30

4 days

C max, AUC, half-life, and CL/F

Rico 2014d [38]

2-period cohort

Bemiparin

3500 IU

48

n = 25 CrCl > 80

n = 8 50 ≤ CrCl ≤ 80

n = 7 30 ≤ CrCl < 50

n = 8 CrCl < 30

Persons with normal renal function had no medical history

4 days

C max, AUC, half-life, and CL/F

Alban 2013e [39]

Cohort

Certoparin

3000 IU

24

n = 12 normal renal function

n = 12 CrCl < 30

 

5 days

C max, AUC, half-life

Polkinhorne 2002e [40]

Randomized

Enoxaparin 4000 IU

Dalteparin 2500 IU

21 HD

Each drug

n = 7

Thrice-weekly hemodialysis patients

4 weeks

Anti-Xa activity 1, 2, 3, 4, 24, and 28 h postinjection

Brown 2010e [41]

Cohort

Enoxaparin 3000 IU

12 CVVH

NA

ICU patients receiving CVVH 30 ml/kg/h

9 daysg

Trough anti-Xa levels

All studies administered a once daily dosage. Peak anti-Xa: activity 4 h postinjection in all studies

CrCl was estimated using the aCockroft Gault formula; bMDRD formula; cformula: (urine creatinine (mg/dl) × 24 h urine volume (ml)/1440 min)/(Ʃ[serum creatinine from days 1, 4, and 5 (mg/dl)]/3); dformula: urine creatinine concentration × 24 h collected urine volume/plasma creatinine concentration × 24 × 60. eCrCl formula is not mentioned. fMedian length of stay. gTime between first and last anti-Xa in whole population

ICU intensive care unit, CrCl creatinine clearance in ml/min, IQR interquartile range, n number of patients, C max maximum concentration, AUC area under the curve, BMI body mass index, CL/F apparent total body clearance, HD hemodialysis, CVVH continuous venovenous hemofiltration

All studies were conducted prospectively. Two were randomized trials, and eight were cohort studies. Only one study did report clear prespecified primary outcomes. The number of patients ranged between 12 and 138. Three studies only included patients on an intensive care unit (ICU), and three studies only included elderly patients (Table 1). The follow-up length per patient was 4 days to 3 weeks. Accumulation was mainly assessed by measuring peak anti-Xa activity or trough anti-Xa activity (Table 2). Six studies reported clinical outcomes like hemorrhagic events, thrombosis, and mortality rates.
Table 2

Outcomes of included studies

LMWH

Parameter

Results

Dalteparin 5000 IU [31]

Trough anti-Xa

Three patients value(s) > detection threshold; none above accumulation threshold

Peak anti-Xa

Mean 0.30 U/ml (95 % CI 0.27–0.33)

 

Day 1

Day 10

Dalteparin 2500, 5000, and 7500 IU [32]

 

CrCl > 60

CrCl 30–59

CrCl < 30

CrCl > 60

CrCl 30–59

CrCl < 30

Peak anti-Xa (range)

0.28b (0.20–0.32)

0.31b (0.23–0.46)

0.28b (0.23–0.33)

0.27a,b (0.16–0.35)

0.48a,b (0.31–0.51)

0.39a,b (0.31–0.50)

Dalteparin 5000 IU [33]

Trough anti-Xa

Seven patients value(s) > detection threshold; none above accumulation threshold

 

Day 3

Day 10

Day 17

Peak anti-Xa (range)

0.29 (0.20–0.42)a

0.35 (0.24–0.43)a

0.34 (0.27–0.45)a

Dalteparin 2500 and 5000 IU [34]

 

Day 6

CrCl > 60

CrCl 30–59

CrCl < 30

Peak anti-Xa (range)

0.030 (0.086)b

0.033 (0.075)b

0.048 (0.084)b

 

Day 1

Day 8

p value

Enoxaparin 4000 IU

Tinzaparin 4500 IU [35]

 

Enoxaparin

Tinzaparin

Enoxaparin

Tinzaparin

Enoxaparin

Tinzaparin

C max

0.55 (0.14)

0.44 (0.16)

0.67 (0.23)

0.46 (0.19)

<0.001

0.296

AUC

354 (119)

252 (103)

447 (218)

273 (111)

<0.001

0.11

Trough

0.06 (0.06)

0.05 (0.04)

0.11 (0.10)

0.06 (0.06)

0.013

0.17

Enoxaparin 4000 IU [36]

 

CrCl 51–80

CrCl 41–50

CrCl 31–40

CrCl 20–30

 

Anti-Xamax 1–10

0.60 (0.16)

0.61 (0.17)

0.61 (0.24)

0.72 (0.27)

 

p value

0.030c

0.039c

0.039c

Ref

Enoxaparin 4000 IU [37]

 

Severe RI

C max

10–35 % higher

AUC(0–24)

65 % higher (day 4)

CL/F

27 % (day 1), 39 % (day 4)

t 1/2λz

Increased with the degree of RI (p < 0.012)

Bemiparin 3500 IU [38]

 

Severe RI

C max

Higher

t 1/2

2–4 h prolonged

CL/F

Lower

AUC

Increased with the degree of RI

Certoparin 3000 IU [39]

 

Severe RI

Ratio severe RI/normal renal function

C max day 5

0.27 (range 0.16–0.70)

1.39 (95 % CI 1.04–1.85)

AUC(0–24)

2.28 (range 1.35–5.11)

1.52 (95 % CI 1.07–2.17)

Enoxaparin 4000 IU, Dalteparin 2500 IU [40]

 

Week 1a

Week 4a

 

Dalteparin

Enoxaparin

Dalteparin

Enoxaparin

Anti-Xa (SEM)

0.2 (0.035)

0.38 (0.028)

0.26 (0.038)

0.40 (0.055)

Enoxaparin 3000 IU [41]

Trough anti-Xa

Mean 0.11 (range 0.01–0.27, SD 0.07). None above accumulation threshold.

All studies administered a once daily dosage. Peak anti-Xa: activity 4 h postinjection in all studies (all anti-Xa activity in IU/ml

IQR interquartile range, CrCl creatinine clearance in ml/min, C max maximum concentration, AUC area under the curve, Anti-Xa max 1–10 maximum anti-Xa activity in 10 days, AUC (0–24) area under the 24 h plasma activity time curve, CL/F apparent total body clearance, RI renal insufficiency, t 1/2 elimination half-life, t 1/2λz apparent terminal elimination half-life, SEM standard error of the mean

aNo significant changes between day 1 and day x

bNo significant changes between groups on day x

cCompared to CrCl 20–30 ml/min

Dalteparin

Dalteparin accumulation was studied in five articles. In patients on a general medical or surgical ward, no accumulation was found in a total of 157 patients by measuring peak anti-Xa activity on day 6 or day 10 [32, 34].

At the ICU, trough and peak anti-Xa activity did not show accumulation on day 9 or day 12 in a total of 157 patients not undergoing CVVH [31, 33].

Also in hemodialysis patients (n = 7) prescribed 2500 IU dalteparin during hemodialysis sessions for 4 weeks, anti-Xa activity at different time points (1, 2, 3, 4, 24, and 28 h postinjection) were not significantly different between week 1 and week 4 [40]. The patients underwent hemodialysis sessions three times a week for 4 h.

Enoxaparin

Three studies of which two in patients older than 75 years examined enoxaparin accumulation in, respectively, 125, 28, and 48 non-dialysis patients [35, 36, 37]. The studies in the elderly with CrCl 20–50 ml/min found a significantly higher maximum concentration (C max), area under the curve (AUC), and trough anti-Xa activity (24 h postinjection) after 8 days administration and a higher peak anti-Xa activity after 10 days, compared to patients with better renal function [35, 36]. The other study in patients with different severity of renal insufficiency found accumulation (a significantly higher C max, longer half-life, higher AUC) already on day 4 in patients with CrCl ≤ 30 ml/min [37].

Hemodialysis patients (n = 7) prescribed 40 mg enoxaparin at hemodialysis sessions for 4 weeks, anti-Xa activity at different time points postinjection were not significantly different between week 1 and week 4 [40]. Also in ICU patients (n = 12) undergoing CVVH with a flow rate of 30 ml/kg/h, no accumulation of enoxaparin (30 mg daily) was found [41].

Tinzaparin, bemiparin, and certoparin

Administration of 4500 IU tinzaparin for 8 days in 27 patients older than 75 years with CrCl 20–50 ml/min and body weight below 65 kg did not lead to significant changes in C max, AUC, and trough anti-Xa activity (24 h postinjection) [35].

For 3500 IU bemiparin, C max was higher and mean half-life was 2–4 h prolonged in patients with severe renal insufficiency after 4 days administration in 48 patients [38]. AUC significantly increased with the degree of renal insufficiency.

For 3000 IU certoparin, C max and AUC were significantly higher in patients with renal insufficiency compared to healthy controls after 5 days administration in 24 patients [39].

Adverse events

Six studies reported VTEs and bleeding events, although all were underpowered to find significant correlations [31, 32, 33, 34, 35, 36]. In three of these studies, anti-Xa activity was undetectable during bleeding [31, 33, 34]. Five serious bleeding complications were reported when using enoxaparin, but anti-Xa activity in these patients was the same as in those without bleeding (p = 0.77) [36].

Discussion

In this systematic review, we show that prophylactic dosages of dalteparin and tinzaparin did not accumulate in patients with renal insufficiency, while prophylactic dosages of enoxaparin, bemiparin, and certoparin did accumulate. Dalteparin also showed no accumulation in hemodialysis patients. Surprisingly, enoxaparin did not show accumulation in hemodialysis and CVVH patients, which might be due to removal by renal replacement therapy [42]. No data are available for nadroparin in patients with renal insufficiency.

These results are in accordance with studies on therapeutic dosages, except for dalteparin. Dalteparin is the only LMWH that appears to accumulate when used in a therapeutic dosage, while in studies using prophylactic dosages no accumulation was detected [31, 32, 33, 34, 43]. A single-dose study showed reduced elimination of prophylactic dalteparin in patients with renal insufficiency, but apparently clearance is sufficient to prevent accumulation [31, 32, 33, 34, 44].

Data on assessment of accumulation on prophylactic nadroparin in renal insufficiency are lacking. Only one multiple-dose study in six patients with CrCl above 30 ml/min and one single-dose study were conducted [45, 46].

Our findings confirm the theory that accumulation seems to depend on the mean molecular weight of LMWHs as shown in Table 3. LMWHs with the lowest molecular weight (enoxaparin, bemiparin, certoparin, and nadroparin) all showed accumulation in a therapeutic dosage and a prophylactic dosage. Tinzaparin (the LMWH with the highest mean molecular weight) has shown not to accumulate in neither therapeutic nor prophylactic dosage. The most likely explanation for this counterintuitive relationship between size and accumulation is that the larger molecules are less dependent on renal clearance [4, 28, 49, 50].
Table 3

Accumulation dependency on molecular weight

LMWH

Mean molecular weight (Da) [13, 47]

Accumulation therapeutic

Accumulation prophylactic

Bemiparin

3600

CrCl < 30 ml/min [38]

CrCl < 30 ml/min [38]

Certoparin

3800

CrCl < 30 ml/min [48]

CrCl < 30 ml/min [39]

Nadroparin

4300

Yesa [20]

No conclusionb

Enoxaparin

4500

CrCl < 30 ml/min [21, 22, 23, 24]

CrCl < 30 ml/min 4 days [37] and 20–50 ml/min 8 days [35]

Dalteparin

6000

CrCl < 30 ml/min after 6 days [32], but not after 3 [43]

Noc [31, 32, 33, 34]

Tinzaparin

6500

Nod [25, 26]

Nod [35]

CrCl creatinine clearance

aOnly correlation GFR/anti-Xa activity reported, no specific accumulation limit

bOnly one multiple dose study in six patients with CrCl above 30 ml/min and one single intravenous dose study [45, 46]

cLargest study no lower limit for CrCl33

dCrCl > 20 ml/min

In patients undergoing renal replacement therapy, it has been shown that many LMWHs are safe to use even in therapeutic dosages [28, 51]. For assessment of accumulation, only a few studies have been conducted. Most of these studies were excluded from this review as they included a single bolus administration, a therapeutic dosage, or no anti-Xa activity measuring at multiple days. Dalteparin showed accumulation in hemodialysis patients if prescribed in a therapeutic dosage, but not in a prophylactic dosage, whereas accumulation was found for prophylactic dosage in peritoneal dialysis patients [19, 40, 52]. Prophylactic dosages of enoxaparin and prophylactic and therapeutic dosages of nadroparin showed no accumulation in hemodialysis and CVVH patients [40, 41, 53, 54]. Tinzaparin accumulation has been found in a therapeutic dose in hemodialysis patients, but in a prophylactic dose, anti-Xa activity returned to baseline in 24 h [52, 55]. In conclusion, for dalteparin accumulation in renal replacement therapy is comparable to accumulation in patients without renal replacement therapy, but in other LMWHs accumulation in renal replacement therapy seems not to depend on mean molecular weight of LMWHs. The mechanism for accumulation in renal replacement therapy is unknown, but the highly negative charge of LMWHs might play a role [52]. More studies are needed to assess LMWH accumulation in patients on renal replacement therapy.

The strength of this review is first that we included only articles that objectively observed accumulation based on anti-Xa activity rather than an accumulation prediction based on the half-life or the time it takes for anti-Xa activity to return to baseline. Second, by including the recent studies on bemiparin and certoparin, this paper confirms the earlier stated theory that accumulation depends on the mean molecular weight of LMWHs.

A limitation might be that we did not include single-dose studies. However, a single-dose study is not suitable for objectively detecting accumulation [28, 32]. A significantly lower clearance or prolonged half-life for a LMWH in a single-dose study does not necessarily indicate that the LMWH accumulates, as is clear from the findings on dalteparin. Furthermore, follow-up of patients in some studies was relatively short (in some studies less than 1 week); however, if LMWHs would accumulate, this would be noticeable already after three dosages. Given the fact that patients tend to be discharged from the hospital within a few days, it is hardly possible to perform clinical studies with longer follow-up.

Another limitation might be that the risk of bias could not be assessed accurately. Considering bias across studies, we feel that a publication bias seems unlikely since both negative and positive outcomes in studies on accumulation have news value, and we included two abstracts of unpublished data. Furthermore, a possible confounder could be the difference in renal insufficiency onset (acute vs chronic) in different studies; however, there is no evidence that this can cause variance in anti-Xa activity.

A major limitation of all studies is that anti-Xa activity rather than hard clinical endpoints were studied. Although a study on hard clinical endpoints in patients with renal insufficiency is probably not feasible due to large numbers needed, it should be taken into account that the correlation between anti-Xa activity and occurrence of bleeding or VTE is not unambiguous [56, 57, 58, 59, 60]. The therapeutic and prophylactic target levels of anti-Xa activity are not supported by evidence of trials, but they are rather based on expert opinions [61, 62]. We also found in our review that in six studies that reported clinical outcomes, none of the patients with bleeding had higher anti-Xa activity than patients without bleeding [31, 32, 33, 34, 35, 36]. However, the anti-Xa activity is considered to be the best test available to measure LMWH activity and to detect accumulation of LMWHs [4, 63].

In conclusion, for several LMWHs the guidelines that recommend dose reduction for prophylactic use in patients with renal insufficiency are evidence based, except for dalteparin, tinzaparin, and nadroparin. We recommend a dose reduction for prophylactic use of enoxaparin, bemiparin, and certoparin in patients with CrCl below 30 ml/min [24, 28, 29, 38, 39]. Prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction. Studies are needed to assess accumulation of prophylactic dosages of nadroparin and for all LMWHs in patients undergoing renal replacement therapy.

Notes

Acknowledgments

This work was funded by the Dutch Kidney Foundation (Safety of medication in renal insufficiency, MV 13.36)

Authors’ Contributions

F. Atiq contributed to the conception and design of the work, data acquisition and analysis, and writing of the manuscript. P.M.L.A. van den Bemt and F.W.G. Leebeek contributed to the conception and design of the work and revised the manuscript critically. T. van Gelder contributed to the conception and design of the work and data analysis and revised the manuscript critically. J. Versmissen contributed to the conception and design of the work, data acquisition and analysis, and writing and revising of the manuscript. All authors approved the final version of the manuscript.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

228_2015_1880_MOESM1_ESM.docx (52 kb)
ESM 1 (DOCX 51 kb)

References

  1. 1.
    Hirsh J, Levine MN (1992) Low molecular weight heparin. Blood 79(1):1–17PubMedGoogle Scholar
  2. 2.
    Hetzel GR, Sucker C (2005) The heparins: all a nephrologist should know. Nephrol Dial Transplant 20(10):2036–2042PubMedCrossRefGoogle Scholar
  3. 3.
    Weitz JI (1997) Low-molecular-weight heparins. N Engl J Med 337(10):688–698PubMedCrossRefGoogle Scholar
  4. 4.
    Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE (2001) Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119(1 SUPPL):64S–94SPubMedCrossRefGoogle Scholar
  5. 5.
    Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts WH (2001) Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 161(10):1268–1279PubMedCrossRefGoogle Scholar
  6. 6.
    Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP, Briet E (1992) Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 340(8812):152–156PubMedCrossRefGoogle Scholar
  7. 7.
    Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM (1999) Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 130(10):800–809PubMedCrossRefGoogle Scholar
  8. 8.
    Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA (1996) A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 335(10):701–707PubMedCrossRefGoogle Scholar
  9. 9.
    Frydman A (1996) Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 26(Suppl 2):24–38PubMedGoogle Scholar
  10. 10.
    Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG (1995) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332(20):1330–1335PubMedCrossRefGoogle Scholar
  11. 11.
    Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, Manthous CA (2004) Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest 125(3):856–863PubMedCrossRefGoogle Scholar
  12. 12.
    Davis R, Faulds D (1997) Nadroparin calcium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders. Drugs Aging 10(4):299–322PubMedCrossRefGoogle Scholar
  13. 13.
    Boneu B (2000) Low molecular weight heparins: are they superior to unfractionated heparins to prevent and to treat deep vein thrombosis? Thromb Res 100(2):V113–V120PubMedCrossRefGoogle Scholar
  14. 14.
    van Dongen CJ, van den Belt AG, Prins MH, Lensing AW (2004) Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 4, Cd001100. doi: 10.1002/14651858.CD001100.pub2 PubMedGoogle Scholar
  15. 15.
    Samama MM, Gerotziafas GT (2000) Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 26(Suppl 1):31–38PubMedCrossRefGoogle Scholar
  16. 16.
    Collignon F, Frydman A, Caplain H, Ozoux ML, Le Roux Y, Bouthier J, Thebault JJ (1995) Comparison of the pharmacokinetic profiles of three low molecular mass heparins–dalteparin, enoxaparin and nadroparin–administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 73(4):630–640PubMedGoogle Scholar
  17. 17.
    Boneu B, Caranobe C, Sie P (1990) Pharmacokinetics of heparin and low molecular weight heparin. Baillieres Clin Haematol 3(3):531–544PubMedCrossRefGoogle Scholar
  18. 18.
    Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 SUPPL):188S–203SPubMedCrossRefGoogle Scholar
  19. 19.
    Schmid P, Brodmann D, Fischer AG, Wuillemin WA (2010) Prospective observational cohort study of bioaccumulation of dalteparin at a prophylactic dose in patients with peritoneal dialysis. J Thromb Haemost 8(4):850–852PubMedCrossRefGoogle Scholar
  20. 20.
    Mismetti P, Laporte-Simitsidis S, Navarro C, Sie P, D’Azemar P, Necciari J, Duret JP, Gaud C, Decousus H, Boneu B (1998) Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin). Thromb Haemost 79(6):1162–1165PubMedGoogle Scholar
  21. 21.
    Becker RC, Spencer FA, Gibson M, Rush JE, Sanderink G, Murphy SA, Ball SP, Antman EM, Investigators TA (2002) Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J 143(5):753–759PubMedCrossRefGoogle Scholar
  22. 22.
    Bazinet A, Almanric K, Brunet C, Turcotte I, Martineau J, Caron S, Blais N, Lalonde L (2005) Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 116(1):41–50PubMedCrossRefGoogle Scholar
  23. 23.
    Chow SL, Zammit K, West K, Dannenhoffer M, Lopez-Candales A (2003) Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin. J Clin Pharmacol 43(6):586–590PubMedCrossRefGoogle Scholar
  24. 24.
    Lim W, Dentali F, Eikelboom JW, Crowther MA (2006) Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 144(9):673–684PubMedCrossRefGoogle Scholar
  25. 25.
    Siguret V, Pautas E, Fevrier M, Wipff C, Durand-Gasselin B, Laurent M, Andruex JP, D’Urso M, Gaussem P (2000) Elderly patients treated with tinzaparin (innohep(registered trademark)) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost 84(5):800–804PubMedGoogle Scholar
  26. 26.
    Pautas E, Gouin I, Bellot O, Andreux JP, Siguret V (2002) Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients. Drug Saf 25(10):725–733PubMedCrossRefGoogle Scholar
  27. 27.
    Horlocker TT, Heit JA (1997) Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg 85(4):874–885PubMedGoogle Scholar
  28. 28.
    Schmid P, Fischer AG, Wuillemin WA (2009) Low-molecular-weight heparin in patients with renal insufficiency. Swiss Med Wkly 139(31–32):438–452PubMedGoogle Scholar
  29. 29.
    Nutescu EA, Spinler SA, Wittkowsky A, Dager WE (2009) Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 43(6):1064–1083PubMedCrossRefGoogle Scholar
  30. 30.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7), e1000097. doi: 10.1371/journal.pmed.1000097 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Rabbat CG, Cook DJ, Crowther MA, McDonald E, Clarke F, Meade MO, Lee KA, Cook RJ (2005) Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency. J Crit Care 20(4):357–363. doi: 10.1016/j.jcrc.2005.09.009 PubMedCrossRefGoogle Scholar
  32. 32.
    Schmid P, Brodmann D, Fischer AG, Wuillemin WA (2009) Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function. J Thromb Haemost 7(4):552–558PubMedCrossRefGoogle Scholar
  33. 33.
    Douketis J, Cook D, Meade M, Guyatt G, Geerts W, Skrobik Y, Albert M, Granton J, Hebert P, Pagliarello G, Marshall J, Fowler R, Freitag A, Rabbat C, Anderson D, Zytaruk N, Heels-Ansdell D, Crowther M (2008) Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med 168(16):1805–1812PubMedCrossRefGoogle Scholar
  34. 34.
    Tincani E, Mannucci C, Casolari B, Turrini F, Crowther MA, Prisco D, Cenci AM, Bondi M (2006) Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study. Haematologica 91(7):976–979PubMedGoogle Scholar
  35. 35.
    Mahe I, Aghassarian M, Drouet L, Bal Dit-Sollier C, Lacut K, Heilmann JJ, Mottier D, Bergmann JF (2007) Tinzaparin and enoxaparin given at prophylactic dose for 8 days in medical elderly patients with impaired renal function. A comparative pharmacokinetic study. Thromb Haemost 97(4):581–586PubMedGoogle Scholar
  36. 36.
    Mahe I, Gouin-Thibault I, Drouet L, Simoneau G, Di Castillo H, Siguret V, Bergmann JF, Pautas E (2007) Elderly medical patients treated with prophylactic dosages of enoxaparin: influence of renal function on anti-Xa activity level. Drugs Aging 24(1):63–71PubMedCrossRefGoogle Scholar
  37. 37.
    Sanderink GJCM, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX (2002) Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 105(3):225–231PubMedCrossRefGoogle Scholar
  38. 38.
    Rico S, Antonijoan RM, Ballester MR, Gutierro I, Ayani I, Martinez-Gonzalez J, Borrell M, Fontcuberta J, Gich I (2014) Pharmacodynamics assessment of bemiparin after multiple prophylactic and single therapeutic doses in adult and elderly healthy volunteers and in subjects with varying degrees of renal impairment. Thromb Res 133(6):1029–1038PubMedCrossRefGoogle Scholar
  39. 39.
    Alban S, Peterfai E, Melzer N, Hagedorn I, De Mey C (2013) Conventional prophylactic doses of certoparin do not cause exaggerated aXa-exposure in patients with severe renal insufficiency. Hamostaseologie 33(1):A65Google Scholar
  40. 40.
    Polkinghorne KR, McMahon LP, Becker GJ (2002) Pharmacokinetic studies of dalteparin (Fragmin), enoxaparin (Clexane), and danaparoid sodium (Orgaran) in stable chronic hemodialysis patients. Am J Kidney Dis 40(5):990–995PubMedCrossRefGoogle Scholar
  41. 41.
    Brown LS, Bourne RS, Kitchen S, VanVeen J, Byrne S (2010) A service evaluation of venous thromboembolism prophylaxis with low molecular weight heparin (LMWH) in intensive care patients receiving continuous renal replacement therapy. Intensive Care Med 36:S293Google Scholar
  42. 42.
    Isla A, Gascon AR, Maynar J, Arzuaga A, Corral E, Martin A, Solinis MA, Munoz JL (2005) In vitro and in vivo evaluation of enoxaparin removal by continuous renal replacement therapies with acrylonitrile and polysulfone membranes. Clin Ther 27(9):1444–1451. doi: 10.1016/j.clinthera.2005.09.008 PubMedCrossRefGoogle Scholar
  43. 43.
    Shprecher AR, Cheng-Lai A, Madsen EM, Cohen HW, Sinnett MJ, Wong ST, Billett HH (2005) Peak antifactor xa activity produced by dalteparin treatment in patients with renal impairment compared with controls. Pharmacotherapy 25(6):817–822PubMedCrossRefGoogle Scholar
  44. 44.
    Stobe J, Siegemund A, Achenbach H, Preiss C, Preiss R (2006) Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency. Int J Clin Pharmacol Ther 44(10):455–465PubMedCrossRefGoogle Scholar
  45. 45.
    Goudable C, Saivin S, Houin G, Sie P, Boneu B, Tonthat H, Suc JM (1991) Pharmacokinetics of a low molecular weight heparin (Fraxiparine) in various stages of chronic renal failure. Nephron 59(4):543–545PubMedCrossRefGoogle Scholar
  46. 46.
    Alhenc-Gelas M, Rossert J, Jacquot C, Aiach M (1995) Pharmacokinetic study of the low-molecular-weight heparin fraxiparin in patients with nephrotic syndrome. Nephron 71(2):149–152PubMedCrossRefGoogle Scholar
  47. 47.
    Martinez-Gonzalez J, Vila L, Rodriguez C (2008) Bemiparin: second-generation, low-molecular-weight heparin for treatment and prophylaxis of venous thromboembolism. Expert Rev Cardiovasc Ther 6(6):793–802PubMedCrossRefGoogle Scholar
  48. 48.
    Alban S, Peterfai E, Melzer N, Hagedorn I, De Mey C (2013) Conventional therapeutic doses of certoparin do not lead to exaggerated aXa-levels in all the patients with severe renal insufficiency. Hamostaseologie 33(1):A64Google Scholar
  49. 49.
    Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC (1998) College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 122(9):799–807PubMedGoogle Scholar
  50. 50.
    Davies RG, Rayment R (2010) Primum non nocere—NICE guidelines on venous thromboembolism. Anaesthesia 65(8):774–778PubMedCrossRefGoogle Scholar
  51. 51.
    Lim W, Cook DJ, Crowther MA (2004) Safety and efficacy of low molecular weight heparins for hem dialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol 15(12):3192–3206PubMedCrossRefGoogle Scholar
  52. 52.
    Rodger MA, Ramsay T, MacKinnon M, Westphal M, Wells PS, McCormick B, Knoll G (2012) Tinzaparin versus dalteparin for periprocedure prophylaxis of thromboembolic events in hemodialysis patients: a randomized trial. Am J Kidney Dis 60(3):427–434PubMedCrossRefGoogle Scholar
  53. 53.
    Hene IZ, Wiertz NR, Van Schilfgaarde M, Wester JPJ, Leyte A, Oudemans-Van Straaten HM (2009) Nadroparin anticoagulation in continuous venovenous hemofiltration (CVVH): kinetics and extracorporeal removal. Intensive Care Med 35:S44Google Scholar
  54. 54.
    Nurmohamed MT, ten Cate J, Stevens P, Hoek JA, Lins RL, ten Cate JW (1991) Long-term efficacy and safety of a low molecular weight heparin in chronic hemodialysis patients. A comparison with standard heparin. ASAIO Trans 37(3):M459–461PubMedGoogle Scholar
  55. 55.
    Hainer JW, Sherrard DJ, Swan SK, Barrett JS, Assaid CA, Fossler MJ, Cox DS, Williams RM, Pittenger AL, Stephenson CA, Hua TA (2002) Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis. Am J Kidney Dis 40(3):531–538PubMedCrossRefGoogle Scholar
  56. 56.
    Levine MN, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M (1989) The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 62(3):940–944PubMedGoogle Scholar
  57. 57.
    Leizorovicz A, Bara L, Samama MM, Haugh MC (1993) Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage. Haemostasis 23(Suppl 1):89–98PubMedGoogle Scholar
  58. 58.
    Brophy DF, Martin EJ, Best AM, Gehr TW, Carr ME (2004) Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction. J Thromb Haemost 2(8):1299–1304PubMedCrossRefGoogle Scholar
  59. 59.
    Brophy DF, Martin EJ, Gehr TW, Carr ME Jr (2004) Enhanced anticoagulant activity of enoxaparin in patients with ESRD as measured by thrombin generation time. Am J Kidney Dis 44(2):270–277PubMedCrossRefGoogle Scholar
  60. 60.
    Al Dieri R, Alban S, Beguin S, Hemker HC (2006) Fixed dosage of low-molecular-weight heparins causes large individual variation in coagulability, only partly correlated to body weight. J Thromb Haemost 4(1):83–89PubMedCrossRefGoogle Scholar
  61. 61.
    Lim W (2010) Using low molecular weight heparin in special patient populations. J Thromb Thrombolysis 29(2):233–240PubMedCrossRefGoogle Scholar
  62. 62.
    Boneu B, de Moerloose P (2001) How and when to monitor a patient treated with low molecular weight heparin. Semin Thromb Hemost 27(5):519–522PubMedCrossRefGoogle Scholar
  63. 63.
    Smith BS, Gandhi PJ (2001) Pharmacokinetics and pharmacodynamics of low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonists in renal failure. J Thromb Thrombolysis 11(1):39–48PubMedCrossRefGoogle Scholar

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© The Author(s) 2015

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Ferdows Atiq
    • 1
  • Patricia M.L.A. van den Bemt
    • 1
  • Frank W.G. Leebeek
    • 2
  • Teun van Gelder
    • 1
    • 3
  • Jorie Versmissen
    • 3
  1. 1.Department of Hospital PharmacyErasmus Medical CenterRotterdamThe Netherlands
  2. 2.Department of HematologyErasmus Medical CenterRotterdamThe Netherlands
  3. 3.Department of Internal MedicineErasmus Medical CenterRotterdamThe Netherlands

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