Low molecular weight heparins in patients with renal insufficiency.
Low molecular weight heparin (LMWH) and unfractionated heparin (UFH) have been evaluated in a large number of randomized clinical trials and have been shown to be safe and effective for the prophylaxis and treatment of thromboembolic disorders, myocardial infarction and unstable angina (Antman et al., 1999; Gould, Dembitzer, Doyle, Hastie, & Garber, 1999). However, a universally accepted standard dose of LMWH for patients with severe renal insufficiency has not been established. Most studies evaluating LMWH have excluded patients with renal insufficiency or have been exceedingly small. There are a few pharmacokinetic studies and limited clinical data to make assumptions about how to dose LMWH in renal insufficiency.
This article will review the current literature regarding the use of LMWH in patients with renal insufficiency with regards to treatment dosages, prophylactic dosages, and dosages used during hemodialysis to prevent thrombosis of the extracorporeal dialysis circuit.
UFH has been the gold standard of anticoagulant care for more than 50 years (Arbit, Goldberg, Gomez-Orellana, & Majuru, 2006). Despite its extensive use in clinical practice, UFH use has several limitations. It has well-known bleeding complications, the ability to induce immune-mediated platelet activation leading to heparin-induced thrombocytopenia (HIT), and a negative effect on bone metabolism leading to heparin-induced osteoporosis (Hirsh & Raschke, 2004). The anticoagulant effect of heparin is monitored by activated partial-thromboplastin time (aPPT), and activated clotting time (ACT). There is wide inter- and intrapatient variability in ACT and aPPT. Therefore, frequent and careful monitoring is required due to an unpredictable dose-response relationship. One benefit that UFH has over LMWH is the antagonistic effects of IV protamine on heparin-induced bleeding. UFH is still considered the anticoagulant of choice during pregnancy, obesity and renal failure due to limited data from clinical trials evaluating the safety and efficacy of the drugs in these special populations (Duplaga, Rivers, & Nutescu, 2001).
Both UFH and LMWH exert their anticoagulant activity predominantly by binding to and exerting a conformational change in antithrombin (antifactor IIa), which accelerates inactivation of factor Xa and thrombin. LMWHs have lower antifactor IIa activity than antifactor Xa activity (Zakarija & Bennett, 2005). LMWHs are derived from UFH by depolymerization to one-third the molecular weight of heparin. Virtually all heparin molecules contain at least 18 saccharide units yielding an antifactor Xa/anti-IIa ratio of 1:1. LMWHs have approximately 15 saccharide units, which decreases its ability to bind to thrombin, giving it an antifactor Xa/anti-IIa ratio of 2:1 to 4:1, depending on the molecular size distribution (Hirsh & Raschke, 2004). This reduction in molecular size reduces the ability of LMWH to bind to protein (Hirsh & Raschke, 2004). Reduced binding to plasma proteins is responsible for the more predictable dose-response relationships, lower incidence of HIT, lower incidence of bone loss, and decreased frequency of major bleeding events (Hirsh & Levine, 1992). LMWHs have improved bioavailability and a longer half-life, which allow for once-twice daily subcutaneous administration based on weight without the need for laboratory monitoring (Hirsh & Raschke, 2004). Laboratory monitoring of LMWH is generally not necessary due to more predictable pharmacokinetic and pharmcodynamic properties. The exception is in special populations such as renal insufficiency, obesity, and pregnancy, where monitoring should be considered (Hirsh & Raschke, 2004). Unlike UFH, the effects of LMWH are not reversible.
There are currently three LMWHs available in Canada: enoxaparin, dalteparin, and tinzaparin (see Table One). Each of these agents is prepared with a different method of depolymerization resulting in different molecular weights, different specific activities (anti-Xa: anti-IIa activities), different rates of plasma clearance and different recommended dosage regimens. They may share some common properties, however, LMWHs are unique and not interchangeable (Hirsh & Levine, 1992). There is a hypothesis that the lower the molecular weight (such as enoxaparin), the more a LMWH depends on renal elimination and may account for the various findings discussed in this article (Mahe, 2007a).
Table One. The three low molecular weight heparins (LMWH) available in Canada Agent Average Intravenous Anti-Xa Molecular half-life to Weight (Minutes) Anti-IIa (Da) Enoxaparin 4500 129-180 2.7:1 Dalteparin 5000 119-139 2.0:1 Tinzaparin 4900 111 1.9:1
Monitoring and anti-Xa levels in special populations
It is not possible to measure LMWH levels directly, therefore, most studies use surrogate biologic markers such as antifactor Xa activity. Appropriate timing, frequency and desired therapeutic target range of antifactor Xa activity are not clearly defined and remain controversial (Duplaga et al., 2001). Despite these limitations, antifactor Xa levels have been shown to be inversely related to thrombus propagation and the development of thrombosis (Alhenc-Gelas et al., 1994; Levie et al., 1989). Measurements of antifactor Xa levels near their peak (four hours) appear to have a stronger correlation with safety and efficacy than through levels obtained just prior to administration (Harenberg, 2004). For suggested peak anti-Xa levels (taken four hours after subcutaneous injection) for all LMWHs see Table Two. Evidence suggests an increased risk of bleeding with levels above 0.8-1.0/mL (Nieuwenhuis, Albada, Banga, & Sixma, 1991).
Table Two. Suggested peak anti-Xa levels (taken four hours after subcutaneous injection) for all low molecular weight heparins (LMWHs) Use Suggested peak Reference anti-Xa levels Prevention of venous 0.1-0.2 U/mL Aguilar & Goldhaber, 1999 thromboembolism Treatment of venous a. Twice daily dosing: Harenberg, 2004 thromboembolism 0.5-1.1 U/mL b. Once daily dosing: Harenberg, 2004 0.8-1.6 U/mL
Several small pharmacokinetic studies of the LMWH enoxaparin have demonstrated there is a delay in drug elimination in patients with renal insufficiency resulting in accumulation of drug and effect. This accumulation could place these patients at an increased risk of bleeding. However, there are conflicting data regarding the pharmacokinetics of enoxaparin in renal insufficiency with regards to half-life and accumulation kinetics.
Review of literature
Lim, Dentali, Eikelboom, and Crowther (2006) conducted a metaanalysis to compare risk of major bleeding and levels of antifactor Xa levels in patients with creatinine clearance (CrCl) < 30 mL/min versus patients with CrCl > 30 mL/min. In the primary analysis of 4,971 patients, of which 416 had a CrCl < 30 mL/min, enoxaparin was associated with an increased risk of bleeding (5.0% versus 2.4%; odds ratio [OR] 2.3; 95% CI, 1.2 to 4.3; p=0.01). However, there was clear evidence of statistical heterogeneity ([I.sup.2] = 50.4%; p=0.03) between studies. Eighteen studies of various LMWHs and various dosages were included in the systemic review: eight evaluated treatment doses of enoxaparin, four used a prophylactic dose of enoxaparin, five evaluated adjusted treatment doses of enoxaparin for renal insufficiency, two used tinzaparin, and one used dalteparin. When the data were analyzed according to LMWH agent, major bleeding was found to be increased when full treatment doses of enoxaparin were used (8.3% versus 2.4%; OR, 3.88 [CI, 1.78 to 8.45]). However, when adjusted doses of enoxaparin were used, major bleeding may not of been increased (0.9% versus 1.9%; OR, 0.58 [CI, 0.09 to 3.78]). Data were not analyzed on risk of major bleeding for tinzaparin, dalteparin, and prophylactic doses of enoxaparin due to insufficient studies.
Another analysis of the data for antifactor Xa levels and renal function in four of the studies used therapeutic doses of enoxaparin 1 mg/kg every 12 hours (Bazinet et al., 2005; Becker et al., 2002; Chow, Zammit, West, Dannenhoffer, & Lopez-Candales, 2003; Peng, Eikelboom, Tenni, McQuillan, & Thom, 2004). All four studies found higher peak anti-Xa levels in patients with renal insufficiency (CrCl < 30 mL/min). Mean antifactor Xa levels after a minimum of three doses ranged from 1.27 to 1.58 IU/mL for patients with a CrCl < 30 mL/min compared to the mean antifactor Xa level of 0.91 to 1.06 IU/mL in patients with CrCl > 30 mL/min. This was found to be statistically significant in three of the four studies (Becker et al., 2002; Chow et al., 2003; Peng et al., 2004). These three studies also recommended dose adjustments in renal insufficiency.
Three studies used empirically adjusted-dose enoxaparin (Collet et al., 2003; Collet, Montalescot, Choussat, Lison, & Ankri, 2001; Kruse & Lee, 2004). Two studies treated patients with a CrCl < 30 mL/min with 65% of the 1 mg/kg dose every 12 hours for three doses, then adjusted doses based the antifactor Xa levels (Collet et al., 2003; Collet et al., 2001). The other study treated all patients with 1mg/kg for the initial dose. However, the subsequent doses were based on CrCl (< 30 mL/min were given 0.5 mg/kg every 12 hours and CrCl 30-60 mL/min were given 0.75 mg/kg every 12 hours) (Kruse & Lee, 2004). Mean antifactor Xa levels were 0.65 IU/mL for patients with a CrCl of < 30 mL/min and 0.82 IU/mL for patients with a CrCl of 30-60 ml/min (p < 0.001). All three studies concluded that adjusted doses produce safe therapeutic levels of anti-Xa with no increase in bleeding.
Two studies evaluated therapeutic tinzaparin in elderly patients with renal insufficiency (Pautas, Gouin, Bellot, Andreus, & Siguret, 2002; Siguret et al., 2000). No correlation was found between the peak level of anti-Xa and CrCl. Only one study evaluated therapeutic doses of daltaparin (Shprecher et al., 2005). This study also found no correlation between CrCl and anti-Xa levels.
Lim et al. (2006) concluded that enoxaparin given at therapeutic doses to patients with CrCl < 30 mL/min is associated with a two- to three-fold increased risk of bleeding. Empirical dose adjustments may decrease this risk, however, more studies are needed to draw a definite conclusion and define what this adjustment should be. These conclusions are based on enoxaparin alone due to limited data found with other LMWHs. The few studies that did evaluate other LMWHs did not find the accumulation in renal failure, however, these were relatively small studies conducted over a short period of time. The known differences in the pharmacokinetics of LMWHs may help validate this assumption. This metaanalysis is suggestive of an increased risk of bleeding with the use of enoxaparin, however, it contained many heterogeneous types of studies, different patient populations, different LMWH preparations, and varying assays to measure antifactor Xa levels, and different dosages, thus making the analysis questionable. It did not take into account any other antiplatelet or antithrombin used that could have contributed to the increased bleeding, nor did it consider the fact that uremic patients may have a higher baseline risk of bleeding regardless of therapy. It is hard to form any true conclusions. However, it is likely that unadjusted treatment doses of enoxaparin can cause an increase in bleeding in renal insufficiency.
After the publication of the meta-analysis by Lim et al. (2006), Lachish, Rudensky, Slotki, and Zevin (2007) conducted a prospective study of 19 patients with CrCl < 30 mL/min who had an indication for full anticoagulation. Nineteen patients received an adjusted dose of enoxaparin 1mg/kg subcutaneously every 24 hours (based on renal function) for two or more days. Peak and trough antifactor Xa levels were measured during the enoxaparin treatment. Fourteen of the 19 (74%) patients had peak factor antifactor Xa levels within 0.5-1.0 IU/mL after the first dose. Mean levels after the first dose were not significantly different from the second or third. No bleeding events occurred in this trial. However, five of the 19 patients did have levels lower than the set therapeutic range of the study. The treatment duration of this study was a maximum of three doses. No accumulation was found, however, this might not be apparent in the short term. It seems a reasonable option to adjust the dosage of enoxaparin for renal insufficiency, but more studies of longer timeframes are needed to assess the best way to do this safely and effectively.
Fox et al. (2007) retrospectively analyzed data from the ExTRACT-TIMI 25 Trial to evaluate the impact of renal dysfunction on outcomes in 18,548 patients with ST-segment elevation myocardial infarctions (STEMIs) treated with enoxaparin or UFH. ExTRACT-TIMI was a randomized double-blind trial in which patients were randomized to UFH or enoxaparin. A reduced dose of enoxaparin was given to patients greater than 75 years (0.75 mg/kg) or CrCl < 30 mL/min (N=106). The primary endpoint was death from any cause or nonfatal recurrent myocardial infarction within the first 30 days of randomization, and secondary outcomes included major bleeding, clinically significant minor bleeding, and stroke. In this study, major bleeding was similar in the enoxaparin and UFH groups in patients with CrCl > 90 mL/min. However, as renal function declined, a progressive increase in bleeding was observed with enoxaparin. The authors also recommend that dosage adjustment with CrCl 30-90 mL/min may be required to achieve benefits of administration of enoxaparin while minimizing the risk of bleeding, however, specific recommendations on how to do this were not provided. Despite the increased risk of bleeds, net clinical benefit (death, stroke, and bleeding) in STEMI patients receiving fibrinolytic therapy did not differ between patients treated with enoxaparin or UFH. This was a large study, however, only 106 patients had CrCL < 30 mL/min. These were high-risk patients who received adjunctive antithrombotic therapy that may have increased the risk of bleeding in these patients. This was a retrospective analysis. Therefore, antifactor Xa were not measured and not correlated with outcomes. From the available data, it appears there is accumulation with treatment doses of enoxaparin in renal insufficiency. This accumulation appears to put patients at an increased risk of bleeding. It seems logical to adjust the dosages of enoxaparin for renal failure; however, the precise dose adjustment is not defined. The therapeutic range of enoxaparin is unknown. Therefore, empirically adjusting may put the patient at risk of sub-therapeutic levels (increasing the risk of clot formation) or supratherapeutic levels (increasing the risk of bleeding).
In the meta-analysis by Lim et al. (2006), the incidences of bleeding in the prophylactic dose studies were not evaluated due to insufficient numbers to make an analysis. Three studies were evaluated using prophylactic doses (enoxaparin 40 mg once daily or 30 mg twice daily). One study found no correlation between peak levels of antifactor Xa and creatine clearance (Mahe et al., 2002). Two studies found that elimination was decreased causing higher antifactor Xa levels (Sanderink et al., 2002). No target antifactor Xa levels have been established for prophylactic doses, however, all studies found that peak levels of antifactor Xa remained below the lower limit of the treatment target therapeutic range for LMWH.
Accumulations of LMWH at prophylactic doses have shown conflicting data and depend on the agent used. Tincani et al. (2006) conducted a prospective cohort study to determine the incidence of daltaparin (5000 IU daily) accumulation and bleeding during prophylaxis treatment in 115 elderly patients with renal failure. Antifactor Xa levels were measured on day one and day six. All patients were treated for a minimum of six days and there were no major bleeding events and no thromboembolic events during the study period. This study did not find relationship between the degree of renal impairment and the peak antifactor Xa levels on day six.
Mahe et al. (2007b) conducted another prospective study to analyze the influence of renal function on antifactor Xa levels on 125 consecutive hospitalized acutely ill elderly patients treated with enoxaparin 40 mg/day for venous thromboembolic events with a mean CrCl of 40 mL/min. Antifactor Xa levels were measured on days one to three and again at days four to 10. They found that mean antifactor Xa levels taken on days four to 10 were significantly higher then the levels taken days one to three (p=0.012) suggesting accumulation.
Mahe et al. (2007a) conducted a prospective randomized parallel study comparing prophylactic dose of enoxaparin (40 mg/day) or tinzaparin (4500 IU/day) in 55 elderly patients. Antifactor Xa levels were measured on day one and day eight of treatment. This pharmacokinetic study also suggests that accumulation does not occur with tinzaparin (p=0.29) and does occur with enoxaparin (p=0.001).
It appears from the above trials that the conflicting data concerning the accumulation of LMWH studied may be due to the type of LMWH and that the accumulation is not a class effect.
This may be due to the different molecular weights, and differences in renal excretion or hepatic metabolism of the agents (Mahe et al., 2007a). More trials are needed for a longer duration to form a better conclusion regarding accumulation. The above studies had a maximum of only 10 days follow-up.
Preventing thrombosis of the extracorporeal dialysis circuit
Lim, Cook, and Crowther (2004) conducted an earlier meta-analysis of the safety and efficacy of LMWH for hemodialysis in patients with end stage kidney disease. Randomized controlled trials that compared an LMWH with another anticoagulant during hemodialysis were evaluated. Eleven studies were included in the meta-analysis and clinical outcomes measured included bleeding symptoms or access compression times, extracorporeal thrombosis, antifactor Xa levels and risk of accumulation for a duration of two weeks to 36 months.
When LMWH was compared to UFH, six studies were included in the analysis for bleeding events. Minor and major bleeding events were combined due to the low event rates of bleeding. They found the RR for bleeding with LMWH compared with UFH was not significant (Relative risk [RR] 0.96, CI 0.27 to 3.43, p=0.95).
When LMWH was compared to UFH, five studies were included in the analysis of the extracorporeal thrombosis within the dialysis circuit (two studies used dalteparin, two studies used tinzaparin, and one study used enoxaparin). They found the RR for bleeding with LMWH compared with UFH was not significant (RR 1.15, CI 0.70 to 1.91). There was no significant evidence of accumulation from monitoring antifactor Xa levels. The meta-analysis concluded that all LMWHs appeared as safe and effective as UFH when comparing bleeding and clotting events during chronic hemodialysis.
After the publication of the meta-analysis by Lim et al. (2004), Joannidis et al. (2007) conducted a randomized, prospective, controlled, crossover study in 40 critically ill patients requiring hemodialysis. Patients received a 30 IU bolus of UFH and a maintenance infusion at 7 units/kg/hour or a 0.15 mg/kg bolus of enoxaparin and a 0.05 mg/kg/hour infusion for 72 hours. Then, a washout period of 12 hours was given before the switch. UFH dose was adjusted to maintain an aPPT of 40 to 45 seconds and enoxaparin dose was adjusted to maintain antifactor Xa level of 0.25-0.30 IU/mL. This study also concluded that LMWH enoxaparin is as safe and as effective as UFH. Anticoagulation with enoxaparin resulted in longer filter survival times (31.8 hours for enoxaparin versus 23.5 hours for UFH [p=0.019], without increasing bleeding complications). However, this study had a small sample of patients and a short duration (72 hours). Therefore, accumulation could not be accurately assessed. Enoxaparin has been shown in previous studies of longer durations (8 to 10 days) to show accumulation (Mahe et al., 2007a; Mahe et al., 2007b).
Perry, O'Shea, Byrne, Szczech, and Ortel (2006) conducted a multi-dose pharmacokinetic study of dalteparin in 14 hemodialysis patients. Prophylactic doses of dalteparin (5000 IU) were administered daily for four days. Accumulation did not occur in this study. However, some increases in antifactor Xa levels did show an apparent increase on day four. This study gave all patients the same dosage of dalteparin, regardless of patient weight, it had a very small sample size and had a short duration (four days).
Current data suggest that LMWH can be used safely at prophylactic dosages in renal insufficiency. However, the safety of long-term prophylaxis has not been addressed.
In general, there were many limitations of the meta-analysis by Lim et al. (2006). The more similar the trials included in a meta-analysis, the more likely the meta-analysis will result in valid conclusions. The addition of study protocols that are significantly different from one another makes a meta-analysis less reliable. In this case, there were many differences in the studies with regards to age, concomitant antiplatelet given, number of doses of LMWH administered, and different types of LMWH administered (Lim et al., 2006). There were varying types of assays used to measure antifactor Xa levels, therefore, results may have differed from lab to lab, and different standards were used to measure the incidence of bleeding. Most studies did not enroll consecutive patients, therefore confounding by treatment indication cannot be eliminated. Patients at high risk of bleeding may have been excluded in many of the trials and there were very few patients with severe renal insufficiency included in the analysis. There was a non-uniform patient population in all the studies evaluated. Thus, the conclusions found in this meta-analysis are less reliable and may not be generalizable (Lim et al., 2006).
There are limited data for the LMWHs tinzaparin and daltaparin. Individual LMWHs may behave differently, therefore conclusions about all LMWHs cannot be assumed because most of the data were studied with the use of enoxaparin.
Renal function does affect antifactor Xa levels in patients receiving enoxaparin. Renal insufficiency can cause supratherapeutic levels through accumulation. This may put patients with renal insufficiency receiving this agent at a greater risk of bleeding. No general consensus exists regarding the minimum CrCl that causes a significant risk of accumulation. Antifactor Xa levels are widely used to monitor LMWH in special populations. However, it has not been validated in studies large enough to confirm an effective therapeutic range. There is insufficient evidence to define which levels are associated with an increased risk of thrombosis or increased risk of bleeding (Crowther & Lim, 2007).
Based on the review of literature, it is clear this issue requires further investigation. The data indicate that renal insufficiency does cause accumulation with therapeutic doses of enoxaparin. There are limited data to make the same assumption concerning other LMWHs. The amount of accumulation, as indicated by antifactor Xa levels, does not seem to occur as greatly when the doses of enoxaparin are adjusted empirically for renal insufficiency (CrCl < 60 mL/min), using prophylactic doses and doses required to prevent thrombosis in the hemodialysis extracorporeal circuit. However, data beyond 10 days do not exist, and accumulation over a long period of time may be significant. The use of measuring antifactor Xa levels remains warranted in patients with CrCl < 30 mL/min treated with empirically adjusted doses and prophylactic doses for more than four days. There are no data correlating empirically adjusted doses of enoxaparin with efficacy and, therefore, these doses may put the patient at risk of being subtherapeutic. Until there are better data to suggest otherwise, adjusted doses of enoxaparin are not first choice in patients with renal insufficiency when other options exist. Heparin remains the gold standard of treatment in patients with renal insufficiency.
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RELATED ARTICLE: Teaching sidebar
Unfractionated heparin is a large, naturally occurring anticoagulant injectable medication. It inhibits the activation of thrombin, factor Xa and other clotting factors within the body's clotting pathway.
Low molecular weight heparins
Low molecular weight heparins are a more refined form of heparin and are much newer to the market. These medications are 1/3 the size of unfractionated heparin. These agents primarily inhibit the clotting factor Xa and, therefore, have a more specific activity within the body.
Anti-factor Xa levels
Anti-factor Xa levels: measure of the blood's ability to clot. Specifically, it is a measure of the body's inhibition of factor Xa. It is used to monitor the effect of LMWH.
aPPT: Activated partial thromboplastin time
aPPT: Activated partial thromboplastin time or the time needed for plasma to form a fibrin clot. Used to monitor the effect of unfractionated heparin.
ACT: Activated clotting time
ACT: Activated clotting time: These are usually done at the bedside. It is used to monitor the effect of high-dose unfractionated heparin before, during, and shortly after surgeries that require intense anticoagulation measures.
Heparin induced thrombocytopenia: A condition where platelet levels are depleted in response to antibodies formed against heparin. This results in increased thrombosis and risk of bleeding and is a contraindication to further heparin or LMWH use.
By Jodi Symes, BSc Pharm, RPh, Pharm D Candidate, University of Washington, Clinical Pharmacist, Emergency Medicine, Pharmacy Services, Atlantic Health Sciences Corporation, Saint John, NB
Address correspondence to: Jodi Symes, BSc Pharm, RPh, Pharm D Candidate, Clinical Pharmacist, Emergency Medicine, Pharmacy Services, Atlantic Health Sciences Corporation, Saint John, NB. E-mail: Symjo@reg2.health.nb.ca
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|Title Annotation:||Pharmacy news and reviews|
|Date:||Apr 1, 2008|
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