Low-molecular-weight heparin in patients with renal insufficiency

Background: Low-molecular-weight heparins (LMWH) have been shown to be safer, more effective and more convenient than unfractionated heparin (UFH) in many clinical situations. However, their use is limited in patients with renal insufficiency (RI) due to bioaccumulation. Method: The literature is critically reviewed and known pharmacokinetic properties are summarised. An approach to using LMWH in patients with RI is proposed on the basis of currently available evidence. Results and discussion: Pharmacokinetic data of commonly used LMWH and of UFH are summarised in respect of RI. Most data are known on enoxaparin. A dose reduction is recommended in patients with severe RI.Limited data on dalteparin and tinzaparin suggest that there is less bioaccumulation. However, further studies are needed, in respect of long-term use and clinical end-points in particular.Therearenodataoncertoparinandonly very limited data on nadroparin. A detailed approach is suggested for the use of LMWH in patients with severe RI. Briefly: (1) before using LMWH, evaluate the patient’s renal function, its expected course, imminent interventions, and general bleeding risk; (2) prefer LMWH to UFH in view of better efficacy and lower bleeding risk in general; (3) however, prefer i.v. UFH to s.c. LMWH if a patient is unstable, is awaiting emergency interventions, or has a high bleeding risk, since UFH can be stopped more quickly due to i.v. administration, has a shorter half-life time, and can be effectively antagonised; (4) prefer a well documented LMWH; use established dosing schemes; (5)monitorLMWHwithpeak anti-Xa levels in patients with severe RI regularly, and adjust dose to be in target range; (6) do not use LMWH in patients with severe RI if there is no possibility of measuring anti-Xa levels. Conclusions:LMWHmaybe considered for patients with severe RI. However, experience, judicious choice and careful monitoring of patients with severe RI treated with LMWH are necessary.


Introduction
Low-molecular-weight heparins (LMWH) have been shown to be at least as efficient and safe as, and more convenient than, unfractionated heparin (UFH) for prophylaxis and treatment of venous thromboembolism (VTE) and for therapy of acute cardiovascular diseases [1][2][3][4][5][6][7][8].LMWH have been shown to be associated with better outcome and/or less risk of bleeding than UFH in VTE prophylaxis for orthopaedic, surgical and medical patients [2], in treatment of VTE [3,9] and acute coronary syndrome (ACS) [10,11], and in special patient groups such as cancer patients [12].Long- term administration of LMWH has been shown to be advantageous for VTE prophylaxis in surgical [13] and medical [14] inpatients, and in patients with cancer [12].LMWH have excellent bioavailability of >85% after s.c.injection; in contrast, s.c.administered UFH has low bioavailability of only 15-40% with wide interindividual variability [15].Furthermore, LMWH have a linear elimination pharmacokinetics [15] which renders their pharmacodynamic effect highly predictable and therefore safe in most situations, without the need for coagulation tests to monitor efficacy or safety [16].The risk of heparininduced thrombocytopenia is lower for LMWH than for UFH [17,18].Therefore, LMWH have replaced UFH in most situations [8,19,20].LMWH are among the most used drugs in hospitals, e.g. about 60% of medical inpatients should have a VTE prophylaxis [21] according to current guidelines [2,22].

Abbreviations
However, there are situations such as renal insufficiency (RI, see table 1), under-or overweight, pregnancy, or childhood, in which the pharmacokinetics of LMWH is less well known and the benefit of the use of LMWH less clear.This review focuses on the use of LMWH in patients with RI.Renal insufficiency is a frequent condition in hospitalised patients.About a quarter of medical inhouse patients of a tertiary care hospital have been found to have at least moderate RI; about 10% have severe RI [23].
The use of LMWH instead of UFH has been shown to be effective and safe in preventing extracorporeal circuit thrombosis during haemodialysis in patients with end-stage renal failure [24,25], and LMWH have been widely used in dialysis centres for years.This intermittent use of LMWH has not been reported to involve increased bleeding complications compared to UFH used otherwise [24].However, the adequate dosing of LMWH is less clear for non-dialysis patients with impaired renal function.Furthermore, there are scant data on the use of LMWH in patients on peritoneal dialysis.
UFH is eliminated by (i) a rapid dose-dependent saturable mechanism and (ii) a slower first-order clearance mechanism [15].In contrast, LMWH are known to be metabolised less by the reticuloendothelial system (i) and to depend mainly on the non-saturable renal mechanism (ii) [15].However, e.g.dalteparin, enoxaparin, and nadroparin have various ratios of renal drug clearance in relation to total drug clearance [15]: dalteparin 3%, enoxaparin 6-8%, nadroparin 4%.
Although an animal model has shown that kidneys clear 69% of the administered radioactively marked dalteparin [26], it should be borne in mind that most of this radioactivity detected in the urine is related to non-functional metabolites, since anti-Xa activity of the urine is less than 10% of the applied dose in healthy volunteers [27], which further decreases the influence of renal function on the risk of bioaccumulation.
The ratio of renal clearance in respect of total drug clearance is lower for LMWH with higher mean molecular weight.It can therefore be postulated that the clearance of LMWH with larger molecules such as dalteparin or tinzaparin is less dependent on renal function than it is for LMWH with lower mean molecular weight, such as enoxaparin or nadroparin [1].
In conclusion, LMWH must be individually analyzed and cannot be discussed as a group of drugs concerning pharmacokinetics in patients with RI.

Bleeding risk versus drug efficacy
Bleeding is the major complication risk of both UFH and LMWH [28][29][30][31].Renal function has been shown to decrease with age [23].In addition, age has been shown to be an independent risk factor for major bleeding [28].
Bleeding risk is increased in patients with impaired renal function [32] regardless of the anticoagulant used [7, 30,33].Causes of bleeding in patients with severe RI are multifactorial and are incompletely understood [32].A meta-analysis of enoxaparin studies showed a relative risk of major bleeding events in patients with severe RI of 2.25 (95% CI 1.19-4.27)compared to patients with better renal function [34].
Bleeding risk has been shown to be lower with LMWH than with UFH in general [28], but this is less evident in patients with severe RI.A metaanalysis has shown no difference in bleeding complications of LMWH and UFH for intermittent use in haemodialysis [24].A registry study on therapy of VTE in patients with severe RI has reported no difference concerning fatal bleedings in patients anticoagulated with LMWH compared with those on UFH; however, the use of UFH has been associated with a significantly higher rate of fatal pulmonary embolism if compared to LMWH [9].Another registry of patients with ACS has reported a trend to lower mortality and lower in-hospital major bleeding in patients with severe RI on LMWH compared to UFH [10].A trend towards higher mortality with UFH compared to LMWH in patients with severe RI has also been reported by a sub-group analysis of two randomised controlled trials [7].
Thorevska et al. reported a significantly higher incidence of minor bleeding events (IDR 2.54, 95% CI 1.01-6.36) in patients with a GFR ≤20 ml/min anticoagulated with enoxaparin compared with UFH [33].Nevertheless, the incidence of major bleeding events was comparable.Further, enoxaparin with known bioaccumulation in RI and clear recommendations for dose reductions was used as the LMWH in this study.The study contained no information on dosage; a potential risk of overdosing may be due to missed dose adjustments.No pharmacokinetic data such as anti-Xa levels were shown which might help to verify this possibility.These results of increased bleeding rates may therefore not be transferable to other settings or other LMWH, in particular because other LMWH are known with less bioaccumulation in patients with severe RI.
In conclusion, there is no strong evidence concerning the bleeding risk with LMWH or UFH in patients with severe RI.However, there are several indicators that LMWH are not only equal to UFH but actually safer in patients with severe RI, as they have been shown to be in patients with better renal function.
Dose reductions may be considered to decrease bleeding risk [1].However, reducing the risk of bleeding may increase the risk of losing therapeutic efficacy.Reduced enoxaparin doses with peak anti-Xa levels below 0.5 U/ml involve a higher risk of death and recurrent myocardial infarction at 30 days in patients with ACS [35].A certain level of anti-Xa activity must be achieved, since too low doses of enoxaparin have been shown to be as ineffective as placebo in preventing thromboembolic complications [36].Furthermore, a registry on patients with severe RI treated for VTE has documented that the risk was higher for a fatal thromboembolic event than for fatal bleeding [9].Dose adjustment algorithms must therefore aim to minimise both the risk of bleeding and the risk of thromboembolic complications.Additionally, regular monitoring of anti-Xa levels is necessary [37].

Evaluation of renal function
Official guidelines [38] stratify renal function into 5 stages (table 1).Glomerular filtration rate (GFR) or creatinine clearance (CrCl) can be estimated in steady state situations although there is ongoing discussion concerning the use of measured CrCl instead [39][40][41], and which formula is best in which situation [42,43].It is well known that renal function cannot be evaluated by serum creatinine alone.
The equation by Cockcroft and Gault [44] (adjusted to SI units) is very often used to estimate CrCl: with gender = 1.04 for women and gender = 1.23 for men Its accuracy may be increased for under-or overweight people by adjusting it to standard body surface 1.73 m 2 using a formula by Du Bois and Du Bois to calculate body surface [45]: Official classification of chronic kidney disease of the National Kidney Foundation (NKF) [38].

Monitoring of LMWH
The use of LMWH need not be monitored by anticoagulation tests in most situations due to their predictable pharmacokinetic properties [1,8,16,46].Coagulation tests such as thrombin time or activated partial thromboplastin time (APTT) used for UFH cannot be used for LMWH monitoring.A chromogenic assay measuring the activ-ity of UFH, LMWH or fondaparinux in patient plasma against activated coagulation factor X (anti-Xa activity) is commonly used to monitor treatment.This assay is used in almost all central laboratories in Swiss hospitals.It is noteworthy that the test must be calibrated for each drug specifically.
Peak values 3-5 h after s.c.injection may be used to monitor LMWH [1, 16,47].Ty pical target ranges are summarised in table 2. Adjusting peak anti-Xa levels to dose and body weight facilitates comparison of anti-Xa levels in pharmacokinetic studies [48,49].
Tr ough values before next injection may be used to evaluate safety alone (bioaccumulation).Anti-Xa activity is actually a pharmacodynamic effect that is used as a pharmacokinetic parameter [50].Although there is discussion as to how it may be correlated to clinical events such as bleeding or thromboembolic complications [51][52][53][54][55], this surrogate parameter is the best available for clinical routine and used in most studies.

Pharmacologic aspects A simple pharmacokinetic model
A simple pharmacokinetic model may be helpful to compare various results from studies such as bioaccumulation factor R or apparent elimination half-life time (t½).Resorption of LMWH after s.c.injection is >85%, the distribution volume approximately corresponds to the plasma volume, and elimination has not been shown to be saturable [15].A one-compartment model with first-order elimination kinetics may be described with a simple exponential term that allows calculation of R [56,57] for an achieved steady-state situation dependent on t½ and dosing interval (τ).
In return, t½ may be estimated from known τ and R, if R > 1. -ln(2)

Dosing interval versus half-life time
It is noteworthy that the t½ of most LMWH (3-4 h [15]) is rather short compared to the dosing interval in prophylaxis.This indicates that t½ may be prolonged, e.g.due to RI, without clinically significant bioaccumulation.Furthermore, this may explain why dose recommendations for patients with severe RI do not necessarily have to be the same for prophylactic (low dose every 24 h) and therapeutic (lower dose every 12 h, higher dose every 24 h) use.Clinically significant bioaccumulation due to RI is more likely to occur if LMWH are used in therapeutic dosing schemes.

Single dose versus long-term studies
Pharmacokinetic data of many studies are based on results after application of a single dose of the drug (see table 3).However, it is important to realize that the pharmacokinetic question of bioaccumulation and consequently the clinical questions of efficacy and safety cannot be answered by studies with a single dose design.This is best shown by the divergent t½ determined on days 1 and 4 in the study by Sanderink et al. [58].Studies with a short-term control period of only 2-3 days have a similar limitation.There is a need for long-term studies, best powered for clinical end-points, to acquire evidence.

Discussion of specific drugs
Although LMWH have been shown to be clinically comparable [1], they have different pharmacokinetic properties [15,59] and therefore potentially different pharmacodynamic effects or risks in patients with RI.Unfractionated heparin (UFH) is also briefly mentioned due to its structural and functional analogy.Studies with pharmacokinetic data on LMWH in respect of RI are summarised in table 3. Published or calculated t½ of enoxaparin, nadroparin, dalteparin and tinzaparin are shown in relation to GFR in figure 1.

Unfractionated heparin
Unfractionated heparin (Liquemin ® ) is predominantly administered continuously i.v.UFH is bound to plasma proteins, which considerably in-fluences the effective dose in acute disorders due to the increase of heparin binding proteins.It is deactivated by the reticuloendothelial system and liver heparinases while being excreted in urine in depolymerised and inactive forms [60,61].Because the plasma level of UFH is influenced by so many factors its effect must be monitored by thrombin time, APTT, or anti-Xa activity.
UFH may be used in patients with severe RI using the same monitoring strategy, bearing in mind that patients with severe RI have a higher bleeding risk in general [28].In unstable situations with imminent intervention or with a high bleeding risk, UFH has the advantages (i) of being stoppable very quickly since it is given continuously i.v., (ii) of being eliminated fairly rapidly due to the short t½, and (iii) of having an effective antagonist (protamine sulphate) [62].Hence UFH is often preferred in such special clinical situations.
In summary: UFH may be used in patients with severe RI employing the same monitoring strategy as in patients with no RI.

Certoparin
There are no data on use of certoparin in patients with RI.There is only one report on critically ill patients showing that patients with generally lower anti-Xa activity have better renal function [63].

Dalteparin
Dalteparin (Fragmin ® / Kabi 2165) has one of the largest mean molecular weights of the LMWH.Pharmacokinetic studies have shown that this goes together with a smaller anti-Xa : anti-IIa ratio and a clearance less dependent on renal function [15].
Therapy: Shprecher et al. [64] reported no significant difference between peak anti-Xa activities after the first administration and after 3 days of therapy comparing patients with normal renal function and patients with mean CrCl of 26 ml/min (range .The investigated time frame was however short. Prophylaxis: There are several pharmacokinetic studies [65][66][67][68][69][70] of prophylactically dosed dalteparin (table 3).Tincani et al. have reported surprising results with anti-Xa levels an approximate factor of 10 below levels documented in other studies and measured in our laboratory [67].
A recently published study of dalteparin in ICU patients with severe RI [68,69] has reported anti-Xa levels in the range of 0.29-0.34U/ml for a median of 7 days (IQR 4-12).However, peak anti-Xa levels may be lower in ICU patients compared to patients on general wards, since vasopressors may decrease resorption and therefore bioavailability of s.c.administered drugs [71].
End stage renal disease: The use of dalteparin as an anticoagulant for haemodialysis has become routine after pharmacokinetic and clinical evaluation [72][73][74][75].It can be used at a prophylactic dose of 5000 U/d s.c. for at least 5 days without clinical signs of accumulation such as bleeding [76].Schrader et al. have published a case report on the effective and safe treatment of DVT in a patient on peritoneal dialysis with dalteparin administered intraperitoneally [77].
In summary: Dalteparin has been shown to be a safe anticoagulant for prophylaxis in patients with severe RI for up to 10 days, although for therapy this has been shown only for 3 days and not for a longer period of time.
Therapy: Most studies of enoxaparin have in-volved patients with ACS.ESSENCE and TIMI 11B have shown a general superiority of enoxaparin compared to UFH [78][79][80].Although patients with severe RI should have been excluded from these studies, 2% of the patients included had a CrCl ≤30 ml/min.A post-hoc analysis of these patients [7] has shown a trend towards a higher combined end-point (death, myocardial infarction, urgent revascularisation) compared to patients with normal renal function (25.9% vs. 17.0%,p = 0.09) and a significantly higher risk of bleeding (major haemorrhages 6.6% vs. 1.1%, p <0.0001).However, the risk of major or minor bleeding did not differ whether UFH or LMWH was used (p = 0.56 and p = 0.93 respectively); but there has been a clear trend to a higher mortality of patients with UFH compared to LMWH (p = 0.09).A trend towards a higher bleeding risk and worse outcome with UFH compared to LMWH has been found in a registry of patients with non-ST-segment elevation ACS as well [10].
Collet et al. [81] deduced a simple dosing scheme empirically with a reduction in the calculated regular enoxaparin dose to 65% if CrCl was ≤30 ml/min; this scheme is combined with monitoring of anti-Xa activity and adjustment of the maintenance dose after the third injection of enoxaparin to aim peak anti-Xa levels between 0.5 and 1.0 U/ml.A prospective study applying this scheme has shown a comparable bleeding risk and comparable peak anti-Xa levels [82].
End stage renal disease: Enoxaparin has been shown to be an effective and safe anticoagulant for haemodialysis and haemofiltration [85,86,98,99].Enoxaparin has been studied in two single-dose pharmacokinetic studies [50,100] in patients on peritoneal dialysis.There is a case report of intraperitoneal administration for treatment of VTE in a child on peritoneal dialysis [101].
In summary: Enoxaparin has been studied in patients with severe RI.Dose reductions are recommended, but excessive reduction of the enoxaparin dose has been shown to increase the risk of thromboembolic complications.
Therapy: Mismetti et al. have reported a significant increase in peak anti-Xa activity in subjects with only very mild RI [102].
Prophylaxis: Alhenc-Gelas et al. [103] investigated VTE prophylaxis with nadroparin in 6 patients with nephrotic syndrome.However, renal function was not clearly specified and only declared to be >30 ml/min.
In summary: Limited data on nadroparin have shown bioaccumulation even in patients with mild RI.

Tinzaparin
Tinzaparin (Logiparin ® / Innohep ® / LHN-1) is known to have the largest molecular weight of all LMWH and therefore to be structurally closest to UFH.
Therapy: Tinzaparin has been safely used for up to 10 days in a single-injection-per-day therapeutic regime (175 U/kg/24 h s.c.) without bioaccumulation in patients with severe RI (CrCl 20-29 ml/min, n = 8) [108,109].It was also used in patients with CrCl of 51.2 ± 22.9 ml/min for up to 30 days, with bleeding episodes occurring in only 1.5% [110], a figure comparable with the bleeding risk in patients without RI [28].
End stage renal disease: Tinzaparin has been safely used for haemodialysis even for longterm use [111,112].A detailed pharmacokinetic profile after i.v. and s.c.single dose injections was measured by Hainer et al. in haemodialysis patients [113].
In summary: Available limited data has shown that tinzaparin does not significantly accumulate in severe RI.We postulate that this is related to its larger mean molecular weight compared to other LMWH.

Product monographs
Official Swiss product monographs give warnings and/or dosing suggestions for most LMWH involving patients with severe RI [61].A GFR of 30 ml/min/1.73m 2 has been shown to be a typical cut-off level.Only nadroparin is at the moment formally contraindicated in these patients not on haemodialysis [61].At present there is no Swiss product monograph for tinzaparin.

Proposed strategies
On the basis of growing evidence, various dosing strategies have been proposed for LMWH in patients with RI [1, 2, 22, 114]: a) Use empirically reduced doses of LMWH according to predefined guidelines.b) Monitor anti-Xa activity and adjust the LMWH dose according to a predefined target range.
c) Combination of a) and b) d) Replace LMWH with UFH.However, each LMWH has its own pharmacokinetic profile, a factor to be borne in mind in choosing the best dosing strategy for a particular LMWH.The best strategy for one LMWH may not be the best for another.

ACCP guidelines 2008
The American College of Chest Physicians (ACCP) commented on the use of LMWH in patients with RI in their recently updated guidelines on anticoagulation [1][2][3][4]115].We discuss some quotations in order to emphasise, specify or modify important points on the basis of the current literature discussed in the present review.Comment: These suggestions have a low grade of evidence and may change in time.In particular, a dose reduction by 50% in patients with severe RI may under-dose enoxaparin, as has been shown [89,97].Under-dosage may lead to loss of efficacy with a worse clinical outcome [35,36].Reduction of the mainte- including a prospective evaluation of a dosing scheme [82].However, there are growing data on the use of dalteparin and tinzaparin for patients with severe RI as well, indicating that there is less bioaccumulation with these drugs (table 3, fig.1).Both drugs may therefore be advantageous alternatives for patients with nance dose to 65% [81,82,93]  Evidence of dalteparin and tinzaparin at a prophylactic dose seems to be strong enough to suggest using them without dose adjustments in patients with severe RI, if precautions are followed as outlined in the next chapter.

Summary and conclusion
Therapy and prophylaxis of thromboembolic events intrinsically involve both the risk of bleeding [28] and the risk of thromboembolic complications [35,36].Patients with severe RI have a higher risk of both [7,10].Renal function decreases with age or may be impaired due to disease.About a quarter of in-house medical patients of a tertiary care hospital have at least moderate RI; about 10% have severe RI [23].
Despite the warnings in many product monographs there is increasing knowledge of the degree of bioaccumulation of LMWH in patients with severe RI.Various LMWH exhibit specific molecular and structural attributes due to different production processes [116].Various pharmacokinetic and pharmacodynamic properties have been documented [15,27,117] (see table 3 and fig.1).Dosing strategies in patients with RI may vary depending on which LMWH is used.Bleeding risk, predictable course of the disease, imminent regular or emergency interventions and concomitant drugs influencing the coagulation system must be considered.

Suggested approach to anticoagulation of a patient with RI
Due to the lack of data, no simple dosing suggestion can be given for all LMWH.However, in the light of all the information discussed in this review, we suggest the following approach for the use of LMWH in patients with (severe) RI: i.v.i ntravenously LMWH low-molecular-weight heparin MDRD modification of diet in renal disease

(
140 -age [years]) • weight [kg](eq. 1) CrCl [ml/min] = gender • serum creatinine[μmol/l] dosing of LMWH in patients with severe renal insufficiency is uncertain."[reference 1, page 148S, right column, line 27] "The data on accumulation with LMWHs other than enoxaparin are limited."[reference 1, page 148S, right column, line 53] Comment: There are more clinical and pharmacokinetic data on the use of enoxaparin in severe RI than of any other LMWH (table 3), severe RI.Further studies are needed, most importantly prospective trials at a therapeutic dose and with clinical end-points.There are not enough data at present on certoparin and nadroparin to allow their use in patients with severe RI other than in trials.-" In the setting of severe renal insufficiency where therapeutic anticoagulation is required, use of UFH avoids the problems associated with impaired clearance of LMWH preparations."[reference 1, page 149S, left column, line 51] Comment: This strategy truly avoids potential problems of bioaccumulation of LMWH.However, it may avoid the best possible therapy as well.A registry study has shown that the risk of fatal pulmonary embolism exceeds the risk of fatal bleeding in therapeutically anticoagulated patients with severe RI [9].Moreover, LMWH use has been associated with a significantly lower rate of fatal PE when compared with UFH, even in patients with severe RI.There is a risk of underdosage at the start of UFH, especially in acutely ill patients, due to increased plasma levels of heparin-binding proteins.LMWH have been shown to be more effective and safer than UFH in general [1, 3, 10, 115] and, with limited data, even in patients with severe RI [7, 9, 10, 24].-" Although there is no specific CrCl threshold at which the risk for accumulation becomes clinically significant, a CrCl of about 30 ml/ min is a reasonable cutoff value based on the available literature." [reference 1, page 149S, left column, line 54] Comment: This cut-off level may be lower for certain LMWH such as tinzaparin.-" If LMWH is chosen, anti-Xa monitoring and/or dose reduction should be done to ensure that there is no accumulation."[reference 1, page 149S, right column, line 2] Comment: LMWH should not be used in patients with severe RI without the possibility of monitoring anti-Xa activity.Therapy: -" In patients with severe renal insufficiency (CrCl <30 ml/min) who require therapeutic anticoagulation, we suggest the use of UFH instead of LMWH (Grade 2C).If LMWH is used in patients with severe renal insufficiency (CrCl <30 ml/min) who require therapeutic anticoagulation, we suggest using 50% of the recommended dose (Grade 2C)." [reference 1, page 149S, right column, line 34]

Stage GFR (ml/min/1.73 m 2 )D escription
We recommend that renal function be considered when making decisions about the use and/or dose of LMWH, fondaparinux, and other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients, patients with diabetes mellitus, and those at high risk of bleeding (Grade 1A).Depending on the circumstances, we recommend one of the following options in this situation: avoiding the use of an anticoagulant that bioaccumulates in the presence of renal impairment, using a lower dose of the agent, or monitoring the drug level or its anticoagulant effect (Grade 1B)." [reference 2, page 382S, right column, line 6] -" The current recommendation for prophylactic-dose enoxaparin in patients with a CrCl <30 ml/min is 50% of the usual dose (i.e.30mg once daily).No specific recommendations have been made for other LMWH preparations."[reference 1, page 149S, right column, line 25] Comment: Underdosage may be a problem with this dose reduction for enoxaparin, as discussed above.Furthermore, the standard prophylactic dose for enoxaparin is 40 mg/d in Europe, in contrast to obviously 60 (2x30) mg/d in the USA.We would not suggest using enoxaparin 20 mg/d for medical patients.
-E valuate the patient's renal function when starting anticoagulation.Not all patients are in steady state at admission.Reevaluate renal function over time.Evaluate the patient's bleeding risk on the basis of history, clinical status, use of concomitant drugs, imminent interventions, and -where appropriate -coagulation tests.-P refer LMWH to UFH on the grounds of better efficacy, safety and convenience.-H owever, prefer i.v.UFH to s.c.LMWH if a patient (i) is unstable, (ii) may need emergency intervention, or (iii) has an increased bleeding risk, on the grounds that i.v.UFH can be stopped quickly, has a short t½, and can be antagonised.-U se only LMWH that have known pharmacokinetic and clinical data for patients with RI, such as, currently, enoxaparin, dalteparin or tinzaparin.Use dosing schemes accordingly.-C hoose therapeutic schemes with injections of LMWH twice daily instead of once daily, to avoid high peak anti-Xa levels.There are scant data on once-daily dosing schemes for most LMWH.