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 accu- mulation 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 accumula- tion. 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- (REPRINTED) ARCH INTERN MED/ VOL 162, DEC 9/23, 2002 WWW.ARCHINTERNMED.COM 2605 ©2002 American Medical Association. All rights reserved. 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 mul- tiple-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 pub- lished 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 (REPRINTED) ARCH INTERN MED/ VOL 162, DEC 9/23, 2002 WWW.ARCHINTERNMED.COM 2606 ©2002 American Medical Association.