Is Impaired Renal Function a Contraindication to the Use of Low-Molecular-Weight Heparin?

ORIGINAL INVESTIGATION Is Impaired Renal Function a Contraindication to the Use of Low-Molecular-Weight Heparin?

Jeff Nagge, BScPhm, BSc; Mark Crowther, MD, MSc; Jack Hirsh, MD, FCCP

Background: Because of the risk of accumulation of an- dress our primary objective did not support the use of a ticoagulant effect, it has been suggested that patients with 30-mL/min (0.50-mL/s) cutoff of creatinine clearance to a creatinine clearance of 30 mL/min or less (Յ0.50 mL/s) select individuals at risk of accumulation when LMW hep- should be excluded from treatment with low-molecular- arin is used. Four of the 5 trials support the notion that weight (LMW) heparin, or have anti–factor Xa heparin anti–factor Xa activity of some LMW heparin prepara- level monitoring performed. tions accumulates in patients with impaired creatinine clearance. Tinzaparin sodium, an LMW heparin with a Objective: To assess the appropriateness of this rec- higher-than-average molecular weight distribution, ap- ommendation. pears to be the exception, since it did not exhibit accumulation in patients with creatinine clearances as low as Methods: We performed a systematic search of 20 mL/min (0.33 mL/s). MEDLINE, EMBASE, and International Pharmaceutical Abstracts to identify prospective articles comparing dif- Conclusions: The use of a 30-mL/min (0.50-mL/s) cut- ferences in the pharmacokinetics of LMW heparins in non- off is not justified, on the basis of currently available evi- dialyzed patients with varying degrees of renal func- dence, to select individuals at increased risk of accumulation. Reference lists of retrieved reports were checked for tion when LMW heparin is used. The pharmacokinetic additional articles. response to impaired renal function may differ among LMW heparin preparations. Results: Three single-dose pharmacokinetic trials and 2 multiple-dose deep vein thrombosis (treatment trials met our selection criteria. The 3 trials that could ad- Arch Intern Med. 2002;162:2605-2609

N CONTRAST to the dose-depen- heparin activity assays is limited in many dent clearance of unfractionated centers. The second approach is to replace heparin, the clearance of low- unmonitored LMW heparin therapy with molecular-weight heparin is con- monitored unfractionated heparin therapy sidered to be primarily via renal in patients with a creatinine clearance (CrCl) excretion.1 Consistent with reports in the of less than 30 mL/min (Ͻ0.50 mL/s).5-7 The I 2,3 literature, we have encountered a num- use of a calculated CrCl as a method for ber of cases of severe hemorrhagic screening for patients at high risk of over- complications associated with the use of anticoagulation is attractive because of its LMW heparin in patients with renal im- ease of performance. However, it is not clear pairment. We therefore attempted to de- whether any particular cutoff in CrCl is a velop operational guidelines for the use of threshold below which there is a danger of LMW heparin in patients with renal in- accumulation of the anticoagulant effect of From the Department of sufficiency. LMW heparin. Furthermore, there is evi- Pharmacy, Hamilton Health An informal review of the literature dence that suggests that the different LMW Sciences, Hamilton, Ontario identified 2 approaches to the treatment of heparin preparations currently available may (Mr Nagge); Department of patients with renal impairment who re- have very different risks of bioaccumula- Medicine, St Joseph’s Hospital, quire parenteral anticoagulation. The first tion in patients with impaired renal func- Hamilton (Dr Crowther); and approach is to use anti–factor Xa heparin tion. Hamilton Civic Hospital (anti-Xa) activity to monitor patients with We performed a systematic review of Research Center (Dr Hirsh). renal insufficiency who are treated with LMW heparin usage in patients with renal Mr Nagge is now with the 1,4 Department of Pharmacy, LMW heparin. Problems with this method insufficiency with the goal of determining University Health Network, include (1) that the therapeutic range for whether the commonly recommended 30 Toronto General Hospital, anti-Xa heparin levels has not been vali- mL/min (0.50 mL/s) of CrCl is an appro- Toronto, Ontario. dated and (2) that access to timely anti-Xa priate cutoff to select patients for exclu-

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Characteristics and Results of the Single-Dose Studies Included for Review*

Correlation No. of Between CrCl Patients in Cause of Chronic Mean CrCl, Mean ± SD AUC, Mean ± SD and aXa

Source LMWH Dose and Route Each Group Renal Failure mL/min† aXa U/mL · h t1/2,h Disappearance? Hory et al,14 Cy 222 250 U aXa/kg 10 NA Ͼ50 13.8 ± 4 2.6 ± 0.8 1991 intravenously 9 GN, 5; IN, 1; NS, 3 30-50 13.5 ± 4 3.8 ± 0.8 Yes 8 GN, 4; DN, 3; IN, 1 10-20 14.0 ± 2.9 4.0 ± 1.2 7 GN, 2; DN, 2; IN, 2; Ͻ10 15.6 ± 5 7.2 ± 3.6† NS, 1 Cadroy et al,15 Enoxaparin 50 IU/kg 12 NA 105 1.80 ± 0.46 2.94 ± 0.91 No 1991 sodium subcutaneously 12 GN, 4; DN, 3; IN, 1; 11.4 3.51 ± 1.20‡ 5.12 ± 2.01‡ PY, 2; AM, 1; MY, 1 Goudable et Nadroparin 41.3 IU/kg 12 NA 75-200 5.7 ± 1.0§ 2.2 ± 0.5‡ al,11 1991 calcium intravenously 5 NS, 3; DN, 1; GN, 1 30-50 8.7 ± 1.5 3.0 ± 0.9 No 7 GN, 3; IN, 2; NS, 2 10-20 11.1 ± 3.6 4.6 ± 1.5 7 IN, 4; NS, 2; GN, 1 Ͻ10 9.2 ± 3.4 3.6 ± 0.9

*LMWH indicates low-molecular-weight heparin; CrCI, creatinine clearance; aXa, anti−factor Xa; AUC, area under the concentration time curve; t1/2, elimination half-life; NA, not applicable; GN, glomerulonephritis; NS, nephroangiosclerosis; DN, diabetic nephropathy; IN, interstitial nephritis; AM, amyloidosis; MY, myeloma; and PY, pyelonephritis. †To convert to milliliters per second, multiply by 0.0167. ‡PՅ.001. §PՅ.01.

sion from treatment with LMW heparin, or for anti-Xa DATA EXTRACTION monitoring, if LMW heparin is used. The reports were screened and retrieved by one of us (J.N.). Pre hoc end points of interest were pharmacokinetic measures METHODS that indicate accumulation of anti-Xa activity. For single-dose

studies, the measures of interest were elimination half-life (t1⁄2) SEARCH STRATEGY and area under the concentration time curves (AUCs). For multiple-dose studies, the maximum and minimum concentra- A systematic search was performed to locate articles compar- tions (Cmax and Cmin) and the AUC were extracted. ing differences in the pharmacokinetics of LMW heparins in The correlation coefficient for the relationship of calcu- patients with varying degrees of renal function. MEDLINE lated CrCl and clearance of anti-Xa activity was extracted from (OVID, from 1966 to the week of May 3, 2001), EMBASE (OVID both single- and multiple-dose studies. from 1980 to 2001 week 19), and International Pharmaceuti- cal Abstracts (Silver Platter, from 1970 to April 2001) were searched without language restrictions by means of the free text RESULTS and Medical Subject Headings terms ardeparin, Normiflo௡, dalteparin, Fragmin௡, kabi 2165, enoxaparin, Lovenox௡, Clex- TRIAL CHARACTERISTICS ane௡, PK-10169, nadroparin, Fraxiparin௡, Fraxiparine௡, Cy 216, parnaparin, reviparin, Clivarin௡, tinzaparin, Innohep௡, logipa- The search identified 304 citations that were screened for rin, tedelparin, heparin, low-molecular-weight, kidney failure, re- eligibility, most of which were excluded on the basis of nal failure, creatinine, renal function, and glomerular filtration the publication type (letter, review, or editorial) or study rate. Reference lists of retrieved reports and review articles were population (animal studies or patients receiving hemodi- checked for additional articles. The names of all authors of rel- alysis or hemofiltration). Of the 304 citations, only 9 met evant articles were then used to search the cited reference field our inclusion criteria. Four of the 9 studies were subse- of the Science Citation Index (Institute for Scientific Informa- tion, from 1993 to May 17, 2001). quently excluded for the following reasons. One article published in French8 contained data from the same 27 pa- 9 SELECTION tients who were previously described in English ; thus, only data from the English trial were considered. One abstract Only prospective trials that investigated the administration of contained data that were subsequently published in full.10,11 a LMW heparin to nondialyzed patients with renal impair- Finally, 2 studies published in abstract form only did not ment were selected. An explicit cutoff of CrCl signifying renal provide enough data for evaluation.12,13 impairment was not chosen. We excluded data derived from Three single-dose pharmacokinetic trials and 2 mul- patients undergoing hemodialysis because CrCl could not be tiple-dose deep vein thrombosis treatment trials were eli- calculated for such patients. Data from review articles and ani- gible for inclusion.9,11,14-16 Table 1 highlights the appli- mal studies were not considered. cable findings of the single-dose studies, and Table 2 METHODOLOGIC QUALITY outlines the results of the multiple-dose studies. All studies included for review used chromogenic Potential sources of bias were identified and used as a means to anti-Xa assays for determining plasma LMW heparin lev- explain discrepancies in results between the retrieved studies. els, which is the recommended method of the College

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 2. Characteristics and Results of the Multiple-Dose Studies Included for Review*

No. of Mean ± SD AUC, Correlation

Patients aXa U/mL · h Mean ± SD Cmax, IU/mL Between CrCl in Each Mean CrCl, and aXa Source LMWH Dose and Route Group mL/min† Day 1 Day n Day 1 Day n Disappearance? Mismetti et Nadroparin 180 IU/kg 12 114 ± 15 15.3 ± 5.5 15.0 ± 2.3 1.34 ± 0.40 1.34 ± 0.40 al,16 1998 calcium subcutaneously 12 62 ± 6 17.3 ± 3.0 21.9 ± 4.6§ 1.31 ± 0.29 1.63 ± 0.34‡ r = 0.49‡ 12 71 ± 24 13.5 ± 6.2࿣ 17.4 ± 6.2 1.12 ± 0.37 1.41 ± 0.54 Siguret et al,9 Tinzaparin 175 IU/kg 7 Ͼ50 0.65 ± 0.14 0.71 ± 0.19 2000 sodium subcutaneously 6 40-49 0.72 ± 0.22 0.75 ± 0.19 Not reported No 9 30-39 0.57 ± 0.26 0.60 ± 0.23 8 20-29 0.73 ± 0.16 0.77 ± 0.19

*LMWH indicates low-molecular-weight heparin; CrCl, creatinine clearance; aXa, anti−factor Xa; AUC, area under the concentration time curve; Cmax, maximum concentration; and IU, international aXa units. Day 1 and day n refer to the first and last days of administration, respectively. †To convert to milliliters per second, multiply by 0.0167. ‡PϽ.002. §PϽ.001 vs healthy young volunteers. ࿣PϽ.001 vs healthy elderly volunteers.

of American Pathologists.4 One study used the S 2222 mL/s) (mean, 11.4 mL/min [0.19 mL/s]) for the patients KB VITRUM kit (Kabi Vitrum, Stockholm, Sweden),14 with CRI and 88 to 140 mL/min (1.47-2.34 mL/s) (mean, while 4 studies used the Stachrom-heparin kit (Diagnos- 105 mL/min [1.75 mL/s]) for the healthy subjects. tica Stago, Asnie`res, France).9,11,15,16 The patients with CRI were composed of 8 women and 4 men with a mean age of 58 years, and the healthy SINGLE-DOSE STUDIES volunteers were 5 women and 7 men with a mean age of 23 years. The mean weight of the individuals of each group Hory et al14 compared the pharmacokinetics of a single was not reported.

intravenous dose of Cy 222 (250 U anti-Xa/kg) in 24 non- The mean t1⁄2 in the impaired renal function group was hemodialyzed patients with chronic renal failure with significantly prolonged and the AUC significantly in- those of 10 healthy volunteers.14 The patients were creased compared with the control group. It should be grouped according to their CrCl into stage 1 (n=9, 30-50 noted that the clearance of enoxaparin’s anti-Xa heparin mL/min [0.50-0.84 mL/s]), stage 2 (n=8, 10-30 mL/ effect in the control group was nearly twice that of vol- min [0.17-0.50 mL/s]), and stage 3 (n=7, Ͻ10 mL/min unteers in other kinetic studies of this LMW heparin,17,18 [Ͻ0.17 mL/s]). The authors did not specify the method which may partly explain the apparent accumulation of used to determine CrCl. anti-Xa heparin activity in the CRI group. There was no Patients in stage 1 were on average 13.2 years younger relationship between the severity of renal failure as mea- and 19.8 kg heavier than stage 3 patients. All 9 patients sured by the CrCl and the total clearance of enoxaparin in stage 1 were male, while 3 of 7 stage 3 patients were (r=−0.29, PϾ.5); however, the lack of correlation may be female. A significantly lower mean hemoglobin level was partly explained by the narrow distribution of CrCls in the found in stage 3 patients than in stage 1 or 2 patients (9.6 CRI group. This study indicates that anti-Xa heparin ac- vs 12.1 and 12.7 g/dL, respectively). Baseline character- tivity is prolonged in patients with CrCls between 5 and istics were not provided for the control group. 21 mL/min (0.08 and 0.35 mL/s) after subcutaneous ad- The AUC was similar for all 4 groups. Patients in ministration of enoxaparin. It is not possible to deter-

stage 3 had a significantly prolonged t1⁄2 compared with mine a cutoff point at which the risk of anti-Xa heparin all other groups. The authors stated that CrCl was sig- activity accumulation increases from this study because

nificantly correlated with anti-Xa t1⁄2 (PϽ.002); how- of the narrow range of CrCls studied. ever, no correlation coefficient was provided to indicate Goudable et al11 investigated the pharmacokinetics the strength of correlation. The results suggest that the of nadroparin calcium after a single bolus intravenous clearance of Cy 222’s anti-Xa heparin activity is signifi- injection (41.3 IU/kg) in 3 groups of patients affected by cantly altered in patients with severely impaired renal CRI of varying severity.11 Group A (n=7) was com- function (CrCl Ͻ10 mL/min [0.17 mL/s]) compared with posed of patients receiving hemodialysis with a CrCl of patients with less severe or no renal impairment. The find- less than 10 mL/min, patients in group B (n=7) had a ings suggest that a cutoff of less than 10 mL/min in CrCl CrCl ranging from 10 to 20 mL/min (0.17-0.33 mL/s), would identify patients at risk of significant accumula- and patients in group C (n=5) had a CrCl of 30 to 50 tion of anti-Xa heparin activity. mL/min (0.50-0.84 mL/s). A group of 12 healthy volun- Cadroy et al15 compared the kinetics of a single sub- teers (CrCl, 75-200 mL/min [1.25-3.34 mL/s]) was in- cutaneous dose of enoxaparin sodium (50 IU/kg) in 12 vestigated but not deemed a control group by the inves- healthy volunteers and 12 patients with chronic renal in- tigators because the ages were not matched. The method sufficiency (CRI) who had not yet undergone hemodialy- used to calculate CrCls was not provided. 15 sis. The CrCls were calculated by the Siersback-Nielsen The t1⁄2 and AUC were similar in all 3 CRI groups. A nomogram and ranged from 5 to 21 mL/min (0.08-0.35 significant difference was detected when these variables

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 were compared with those of the healthy subjects, indi- of CrCls (20 to Ͼ50 mL/min [0.33-0.84 mL/s]), indicate cating a faster elimination in the younger, healthy vol- that the anti-Xa heparin effect of tinzaparin does not ap- unteers. No significant correlation existed between CrCl pear to accumulate as CrCl declines. and the clearance of nadroparin in the patients with CRI, Ͻ despite a larger spread of renal function ( 10-50 mL/ COMMENT min [Ͻ0.17-0.84 mL/s]). The results support the no-

tion that the t1⁄2 of nadroparin’s anti-Xa heparin activity LMW heparin preparations are becoming the anticoagu- is prolonged in patients with calculated CrCls of less than lant of choice for the treatment of venous thromboem- 50 mL/min (Ͻ0.84 mL/s). bolism and acute coronary syndromes, as they possess a number of advantages over unfractionated heparin. Un- MULTIPLE-DOSE TRIALS fortunately, LMW heparins also have the disadvantage that they can accumulate in patients with renal failure Mismetti et al16 reported on the differences in pharma- and therefore have the potential to produce serious bleed- cokinetics between 3 groups of 12 individuals treated with ing in such patients. Accordingly, it would be desirable a daily subcutaneous injection of nadroparin calcium (180 to develop guidelines for the management of LMW hep- IU/kg) for 6 to 10 days.16 The first 2 groups were com- arin in patients with renal failure. posed of healthy volunteers differing by age (25±4 and The primary objective of our study was to perform a 65±3 years) and CrCl (114±15 and 62±6 mL/min comprehensive review of the literature to determine whether [1.90±0.25 and 1.04±0.10 mL/s]). The third group was the use of the recommended cutoff of 30 mL/min (0.50 composed of hospitalized patients undergoing treat- mL/s) in CrCl is appropriate to select patients for exclu- ment for acute deep vein thrombosis (mean age, 65±11 sion from treatment with LMW heparins, or for anti-Xa hep- years; CrCl, 76±8 mL/min [1.27±0.13 mL/s]). The au- arin activity monitoring if an LMW heparin is used. Three thors did not state how CrCls were determined. studies included for review investigated patients with a large The Cmax,Cmin, and AUC after the last administra- enough spread in CrCl to evaluate our primary objective. tion of nadroparin were significantly higher in both the There were no data from these 3 trials to support the use deep vein thrombosis group and healthy elderly pa- of the currently recommended cutoff level of 30 mL/min. tients compared with the healthy young group, sugges- In keeping with current views, however, the results of 4 of tive of an accumulation of drug. the 5 trials reviewed support the notion that patients who A correlation coefficient was calculated for 2 com- have a reduction in calculated CrCl are at risk of accumu- parisons. When all groups were considered, the correla- lation of anti-Xa heparin activity when they are treated with tion between the CrCl and the clearance of anti-Xa certain LMW heparins. The exception appears to be the activity was 0.49 (PϽ.002). When the group of patients LMW heparin tinzaparin, which, in a small study, did not with deep vein thrombosis was excluded from the cal- accumulate in patients with calculated CrCls as low as 20 culation, the correlation coefficient increased to 0.69 mL/min (0.33 mL/s). (PϽ.001). This study supports the relationship between The 3 trials that allowed evaluation of the 30-mL/min renal function and the clearance of nadroparin’s anti-Xa (0.50-mL/s) cutoff provided conflicting findings. Hory et heparin effect. However, it does not allow us to address al14 investigated the kinetics of a single dose of intravenously the appropriateness of using a cutoff of 30 mL/min administered Cy 222 to patients grouped according to (0.50 mL/s), because insufficient numbers of patients their CrCl, which ranged from less than 10 mL/min to were studied and few patients had very low CrCls. greater than 50 mL/min. They determined that, despite Siguret et al9 examined the pharmacokinetics of similar AUCs, patients with the most severely impaired tinzaparin sodium (175 IU/kg) administered subcutane- renal function (CrCl Ͻ10 mL/min [Ͻ0.17 mL/s]) had a

ously once daily for 10 days in 30 patients (6 male, 24 significantly prolonged t1⁄2 of anti-Xa activity when com- female) being treated for acute thromboembolic dis- pared with all other groups. Their findings therefore ease.9 Serum creatinine was measured on day 0, and suggest that a cutoff of less than 10 mL/min in CrCl CrCls were calculated by the Cockroft formula. For would identify patients at risk of significant accumula- analysis, the patients were grouped according to their tion of Cy 222. The results of this trial may not be ap- CrCl into ranges of 50 mL/min and greater (Ն0.84 plicable to other LMW heparin preparations, because mL/s) (n=7), between 40 and 49 mL/min (0.67 and Cy 222 has a mean molecular weight of 2500 d, nearly 0.83 mL/s) (n=6), between 30 and 39 mL/min (0.50 50% smaller than the LMW heparins in clinical use to- and 0.66 mL/s) (n=9), and between 20 and 29 mL/min day. The smaller size of Cy 222 likely causes a greater (0.33 and 49 mL/s) (n=8). The breakdown of age, reliance on renal clearance than for the other LMW weight, and sex for each group was not provided. heparins included in this review.19 No increase in mean Cmax values was observed in any In the second study, a single dose of intravenous na- group after 10 days of administration of tinzaparin. The droparin was administered to 3 groups of patients with CRI Ͻ Ͻ Cmax values during the 10 days were similar even when the of varying severity (CrCl, 10 to 50 mL/min [ 0.17 to 0.84 11 group with CrCls greater than 50 mL/min (Ͼ0.84 mL/s) mL/s]). The t1⁄2 and AUC were similar in all 3 CRI groups was compared with the group with CrCls between 20 and but were significantly larger than the same kinetic vari- 30 mL/min (0.33 and 0.50 mL/s). The Cmin and AUC val- ables obtained from a group of healthy subjects, indicat- ues were not provided. The clearance of anti-Xa activity ing a faster elimination in the healthy volunteers. The re- and the CrCl were not correlated. The results of this study, sults of this study suggest that the anti-Xa activity of completed in a group of patients with a wide distribution nadroparin may accumulate in patients with CrCls as high

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 suggests that the type of renal injury should be consid- Table 3. Anticoagulant Profiles and Molecular Weights ered in future investigations. Because of the scarcity of lit- for the Low-Molecular-Weight Heparins Investigated erature in this area, the potentially serious consequences in Studies Included for Review14,20,21 of accumulation, and the increasing use of LMW heparin preparations, kinetic studies for each LMW heparin in Anti−Factor Xa to Agent Anti−Factor IIa Ratio Molecular Weight, d patients with varying degrees of renal insufficiency are urgently required. Enoxaparin sodium 4:1 4371* Nadroparin calcium 3.2:1 4855* Accepted for publication April 3, 2002. Tinzaparin sodium 1.9:1 5866* We thank Pamela Nagge for her editorial assistance. Cy 222 10:1 2500 Corresponding author and reprints: Jeff Nagge, BScPhm, *Determined by gel permeation chromatography. BSc, c/o Toronto General Hospital, Eaton North Wing G-260, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4 as 50 mL/min. Therefore, using a cutoff of 30 mL/min (0.50 (e-mail: [email protected]). mL/s) may miss some patients at risk of accumulation. The third trial that could be used to assess a cutoff REFERENCES of 30 mL/min in CrCl was of the soundest design of all 1. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular- studies included for review. In this multiple-dose trial weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, of tinzaparin in elderly patients being treated for deep efficacy, and safety. Chest. 2001;119(1, suppl):64S-94S. vein thrombosis, a wide range of renal function was in- 2. Busby LT, Weyman A, Rodgers GM. Excessive anticoagulation in patients with Ͼ Ͼ mild renal insufficiency receiving long-term therapeutic enoxaparin. 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Fareed JF, Jeske W, Hoppensteadt D, Clarizio R, Walenga JM. Low-molecular- ure to demonstrate accumulation with one preparation. weight heparins: pharmacologic profile and product differentiation. Am J Car- Furthermore, there is evidence of variability in the phar- diol. 1998;82:3L-10L. 21. Merli GJ. Treatment of deep venous thrombosis and pulmonary embolism with macokinetics of these products in patients with similar de- low molecular weight heparin in the geriatric population. Clin Geriatr Med. 2001; grees of renal impairment as measured by the CrCl. This 17:93-106.

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