intl.elsevierhealth.com/journals/thre

REGULAR ARTICLE

Low-molecular-weight heparins for thetreatment of acute coronary syndrome andvenous thromboembolism in patients with chronicrenal insufficiency

Wendy Lim, Khalid Al Saleh, James D. Douketis*

Department of Medicine, McMaster University and St. Joseph’s Hospital, Hamilton, ON, Canada

Received 4 March 2005; received in revised form 4 March 2005; accepted 8 March 2005Available online 18 July 2005

0049-3848/$ - see front matter D 200doi:10.1016/j.thromres.2005.03.028

* Corresponding author. St. Joseph’sCharlton Ave. East, Hamilton, ON, Can521 6178; fax: +1 905 521 6068.

E-mail address: jdouket@mcmaste

KEYWORDSLow-molecular-weightheparin;Chronic renalinsufficiency;Venousthromboembolism;Acute coronarysyndrome

Abstract The clinical management of patients with renal insufficiency who developan acute coronary syndrome or venous thromboembolism is a common clinicalscenario that is problematic because of the lack of well-designed randomized trialsassessing management strategies in such patients. Impaired renal function iscommon in patients who develop thromboembolic disorders, particularly in elderlypatients in whom renal insufficiency is under-recognized. Low-molecular-weightheparins (LMWHs), which are the most widely used anticoagulant for the treatmentof patients with an acute coronary syndrome or venous thromboembolism, areeliminated primarily by the kidney and, therefore, pose treatment challenges inpatients with impaired renal function. However, there is emerging evidenceregarding the use of LMWHs in patients with impaired renal function suggestingthat some preparations may be safe in such patients. The objective of this review isto discuss the clinical management of patients with renal insufficiency who developan acute coronary syndrome or venous thromboembolism, and to explore similaritiesand differences of LMWHs when used in this clinical setting.D 2005 Elsevier Ltd. All rights reserved.

5 Elsevier Ltd. All rights reserv

Hospital, Room F-541, 50ada, L8N 4A6. Tel.: +1 905

r.ca (J.D. Douketis).

Introduction

The anticoagulant management of patients withan acute coronary syndrome (ACS) or venousthromboembolism (VTE) who also have chronicrenal insufficiency is a challenging scenario be-cause of the lack of evidence-based guidelinesthat inform clinical practice. At dthe end of the

Thrombosis Research (2006) 118, 409—416

ed.

W. Lim et al.410

dayT, clinicians are left with two anticoagulantmanagement options: 1) avoid low-molecular-weight heparins (LMWHs) and instead use unfrac-tionated heparin, or 2) use LMWHs cautiously, withanticoagulant monitoring using anti-(factor) Xalevels. Both options have drawbacks: unfractio-nated heparin requires intravenous administrationand frequent blood testing for anticoagulantmonitoring, and anti-Xa levels are difficult toobtain and interpret for LMWH therapy doseadjustments. Against this background, the objec-tive of this review is to discuss the clinicalmanagement of patients with impaired renalfunction who develop an ACS or VTE, and explorethe use of LMWHs in this clinical setting.

What is the scope of this clinicalproblem?

Renal insufficiency is common in patientswith ACS or VTE

In a study of 163 consecutive outpatients withchronic renal insufficiency at St. Joseph’s Health-care, Hamilton, 44% had ischemic heart disease,33% had peripheral vascular disease, and 10% hadchronic atrial fibrillation [1]. These findings aresupported by a larger Canadian population-basedstudy of patients with chronic renal insufficiency, inwhom 46% had cardiovascular disease at baselineand 20% developed a new cardiovascular eventafter 20 months of follow-up [2]. Conversely, about50% of patients with an ACS have renal insufficiencyor will develop it during the course of their illness[3—5], and in a study of 2200 patients with VTE,52% had mild or moderate renal insufficiency [6].Although these prevalence estimates appear high,this is likely because chronic renal insufficiency isunder-recognized, particularly in the elderly inwhom an ACS and VTE are most common [7,8].

Chronic renal insufficiency isunder-recognized

Elderly patients with a serum creatinine in thenormal laboratory range (usually up to 110 or 120Amol/L) are often misrepresented as havingdnormalT renal function [9]. However, becausecreatinine production decreases as muscle massdeclines with age, the same creatinine valuerepresents a lower glomerular filtration rate(GFR) in an elderly than younger person [10]. Thus,a 75-year-old, 65-kg woman with a dnormalTcreatinine of 115 Amol/L has, in fact, moderate

renal insufficiency (GFR: 55 mL/min). In theNHANES III database, a population-based survey ofclinical and laboratory characteristics, the preva-lence of renal insufficiency increased with age: insubjects aged 70—79 years, a GFR of 60—79 mL/minwas found in 16% of subjects, and a GFR of 30—59mL/min was found in 44% of subjects [11]. In acommunity-based study of 2543 subjects with adnormalT creatinine, a GFR of 60—79 mL/min wasfound in 47% of people aged N70 years [12].Overall, the high prevalence of renal insufficiencyin the elderly underscores the need for judicioususe of LMWHs in such patients who are most likelyto develop an ACS or VTE.

Use of LMWHs in patients with renalinsufficiency

In contrast to unfractionated heparin, which iseliminated through hepatic (reticuloendothelialsystem) and renal mechanisms, LMWHs are pre-dominantly cleared by the kidney. Accumulation ofthe anticoagulant effect of LMWHs (as measuredusing anti-Xa levels), and more importantly, ex-cessive bleeding complications, are concernswhich currently limit LMWH use in patients withrenal insufficiency.

Current management recommendations

Management guidelines for use of LMWHs in patientswith renal insufficiency are inconsistent regardingthe severity of renal disease that would precludeLMWH use [13]. Thus, some experts recommendavoiding LMWHs in patients with moderate-to-severe renal insufficiency, with a GFRb40 mL/min[14,15], and others recommend avoiding LMWHsonly in patients with severe renal insufficiency, witha GFRb30 mL/min [16,17]. Finally, some guidelinesdo not specify the GFR level that warrants avoid-ance of LWMH [18,19]. A recent critical review ofthe literature assessed if current guidelines forLMWH use in patients with renal insufficiency arejustified [20]. In this review, few studies metinclusion criteria, and most studies used prophylac-tic dose LMWH to prevent hemodialysis accessthrombosis in patients with end-stage renal disease(GFRb15 mL/min) [21—25]. The method of asses-sing renal insufficiency was frequently not speci-fied, and varied among the studies. The authorsconcluded that management guidelines are notbased on good quality evidence, and the potentialfor an excessive anticoagulant effect due to accu-mulation of LMWH could not be excluded if LMWHs

Low-molecular-weight heparin in patients with chroric renal insufficiency 411

were given to patients with mild-to-moderate renalinsufficiency (GFR: 30—89 mL/min).

Advantages of LMWHs in patients with ACS orVTE

LMWHs are first-line anticoagulants for the initialtreatment of patients with an ACS or VTE [26—29],and have several advantages over unfractionatedheparin. First, because of predictable pharmacoki-netics, LMWHs are easier to administer with once-daily, weight-based, subcutaneous dose regimensthat do not require laboratory monitoring [30]. Incomparison, unfractionated heparin, which is oftenused in patients with renal insufficiency, hasunpredictable pharmacokinetics and requires fre-quent blood testing for dose adjustments [18].Second, unfractionated heparin requires in-hospitalintravenous administration, whereas LMWH therapycan be given out of hospital [31,32] and is,consequently, more cost-effective than unfractio-nated heparin for the treatment of VTE [33,34].LMWHs have also been found to be more costeffective for the treatment of ACS [35,36]. Third,compared to unfractionated heparin, LMWH thera-py is associated with a lower risk of heparin-induced thrombocytopenia, an infrequent butdevastating thromboembolic complication [37].Finally, and perhaps most important, one LMWH(enoxaparin) has superior antithrombotic efficacycompared to unfractionated heparin in patientswith an ACS [15,38], and its use is endorsed bycardiology consensus groups [26—28]. ShouldLMWHs prove safe in patients with renal insuffi-ciency, they offer a number of therapeutic andpractical advantages over unfractionated heparin.

Practical management considerations

In patients with renal insufficiency in whom treat-ment with LMWHs provides therapeutic advantages,an approach to clinical management would incor-porate several considerations that are illustrated inthe Case Presentation. First, anticoagulant moni-toring can be done with anti-Xa levels measured4 h after a subcutaneous dose of LMWH. Althoughthere is no validated anti-Xa therapeutic range inpatients who receive LMWHs, consensus groups haveendorsed the following parameters: in patientsreceiving twice-daily LMWH (e.g., enoxaparin1 mg/kg BID), the target therapeutic anti-Xa levelis 0.6—1.0 IU/mL; and in patients receiving once-daily LMWH (e.g., tinzaparin 175 IU/kg), the targettherapeutic anti-Xa level is 1.0—2.0 IU/mL [18].Measuring the anti-Xa level after the second or thirdday of treatment can be done to ensure there is no

excessive anticoagulation, especially in patientswith severe renal insufficiency (GFRb30 mL/min).Second, other measures can be undertaken tominimize the risk for anticoagulant-related bleed-ing complications. These measures may include:standing orders on admission of medical patients torecord body weight and calculated GFR, so as toavoid LMWH dose errors; documentation of riskfactors for bleeding (e.g., recent gastrointestinalbleeding, active peptic ulcer disease, thrombocy-topenia), so as to identify patients in whom closerclinical surveillance may be warranted; and avoid-ance of drugs that affect hemostasis (e.g., anti-platelet agents, non-steroidal anti-inflammatorydrugs). Third, consideration may be given toadministering a LMWH preparation that may be lesslikely to accumulate when administered in patientswith renal insufficiency, as outlined below.

Differentiation of LMWHs in patients withrenal insufficiency

The potential for accumulation and an excessiveanticoagulant effect is considered to apply to allLMWHs [18,19]. However, there is emerging evi-dence that some LMWHs may be safer than others.The biological basis for this premise relates to thepolysaccharide chain length of LMWHs: largermolecules are more negatively charged, whichfavors non-renal clearance, and have greater anti-IIa vs. anti-Xa activity, which favors hepatic clear-ance [39,40]. It is, therefore, plausible that as thesize of a LMWH decreases (tinzaparin, 6.8 kD;dalteparin, 5.6 kD; enoxaparin, 4.5 kD; fondapar-inux, 1.7 kD), there is less clearance, and moreaccumulation, in patients with renal insufficiency.With this reasoning, tinzaparin, which is the largestLMWH with the most anti-IIa activity, would havethe most favorable pharmacokinetic profile, where-as fondarinux, the smallest LMWH without any anti-IIa activity, would have the least favorable pharma-cokinetic profile in the setting of renal impairment.The evidence, outlined below, examines the influ-ence of LMWH molecular size and the potential forrenal clearance and accumulation in patients withrenal insufficiency.

Tinzaparin

Tinzaparin is the largest LMWH (6.5 kD) with thefollowing properties [41,42]: anti-Xa-to-anti-IIa,1.6-to-l; peak activity, 3—4 h; half-life, 3.4—4.1h; and undetectable at approximately 24 h. Thereis emerging evidence from 3 studies suggesting thattinzaparin has a favorable safety profile in patients

W. Lim et al.412

with renal insufficiency. In a study in whichtherapeutic-dose tinzaparin was given to 30 elderlypatients (87F6 years) with VTE and a GFR of41F15 mL/min, there was no correlation betweenanti-Xa levels and GFR, thereby suggesting thattinzaparin does not accumulate and cause anexcessive anticoagulant effect in patients with alow GFR [50]. Another study involved 200 elderlypatients (85F7 years) with less severe renaldisease (GFR: 51F23 mL/min) who received ther-apeutic-dose tinzaparin for VTE or arterial throm-boembolism [43]. In this study, there was nocorrelation between anti-Xa levels and GFR. How-ever, the strength of this finding is limited becausethe dose of tinzaparin was decreased in patientswith 4-h post-injection anti-Xa levels N1.3 IU/mL.Consequently, one could not exclude the possibilityof tinzaparin accumulation if the dose had not beendecreased. In a sub-study of a clinical trial involving187 patients with VTE who received tinzaparin andunderwent 4-h post-injection anti-Xa measure-ments after 3 days of treatment [44], an excessiveanticoagulant effect appeared to occur only inpatients with severe renal insufficiency (GFRb30mL/min) in whom tinzaparin clearance decreasedby 24% [45]. Taken together, these findings suggestthat the larger molecular size of tinzaparin makesit less likely to accumulate than other LMWHs inpatients with mild-to-moderate renal insufficiency(GFRN30 mL/min).

Dalteparin

Dalteparin is a smaller LMWH (5.8 kD) thantinzaparin, and has the following properties [46]:anti-Xa-to-anti-IIa, 2.1-to-1; peak activity, 2.8—4.0h; half-life, 2.8—3.8 h; and undetectable at ap-proximately 24 h. Dalteparin is widely used inpatients with VTE [47], particularly in those withcancer [48], and for peri-operative anticoagulationin patients receiving warfarin [49]. The only studiesexamining dalteparin in patients with renal diseaseare in hemodialysis-dependent patients [50—53],with no studies in patients with chronic renalinsufficiency. Based on the size of dalteparin, itwould be expected to have pharmacokinetic prop-erties intermediate between those of enoxaparinand tinzaparin.

Enoxaparin

Enoxaparin is a smaller LMWH (4.5 kD) thandalteparin, and has the following properties [46]:anti-Xa-to-anti-IIa, 2.8-to-1; peak activity, 2.7—3.5h; half-life, 3.5—4.1 h; and undetectable at ap-proximately 30 h. Enoxaparin is as effective or

more effective than unfractionated heparin for thetreatment of an ACS or VTE [15,38,54], and it is themost widely prescribed LMWH in Canada [55]. In asingle-dose pharmacokinetic study involving 12healthy subjects and 12 patients with a GFR of 5—21 mL/min who received enoxaparin 0.5 mg/kgtwice daily (50% of therapeutic dose), the half-lifeof enoxaparin was significantly longer in patientswith chronic renal insufficiency (5.1 vs. 2.9 h;P b0.01) [22]. A sub-study of the TIMI-11A trialinvolved 445 patients with an ACS who receivedenoxaparin in whom trough anti-Xa levels weremeasured after 3 days of treatment [5]. In thisstudy, there was a strong, inverse correlationbetween decreasing GFR and trough anti-Xa levels(R =0.80; P b0.01). In a cohort study of 106 patientswith an ACS who received enoxaparin, patientswith renal disease had a higher risk of majorbleeding (30% vs. 2%; P b0.01) than those withoutrenal disease [3]. These findings are supported by astudy involving 224 patients with an ACS whoreceived enoxaparin [4], in which a 20 Amol/Lcreatinine increase conferred a 40% increase in therisk of major bleeding (OR=1.4; 95% CI: 1.0—2.2).Finally, there are case reports of enoxaparin-associated bleeding in patients with renal insuffi-ciency [56—58], and in a sub-study of the ESSENCEand TIMI-11B trials involving patients with an ACSwho received enoxaparin, the risk of major bleed-ing was higher in patients with renal insufficiency(7% vs. 1%; P b0.01) [59]. Although it is difficult toexclude confounding by a possible increased risk ofbleeding attributable to renal insufficiency itself,these findings support the premise that because ofits small size, enoxaparin is more likely to accu-mulate and cause bleeding complications thanother LMWHs.

Fondaparinux

This novel drug is a 1.7 kD synthetic pentasacchar-ide heparin analogue, with the following properties[60]: 100% anti-Xa activity; peak activity, 3 h; half-life, 17—21 h; and undetectable at approximately36 h. Fondaparinux was recently approved inCanada for VTE prophylaxis after orthopedic sur-gery. It is more effective than enoxaparin inpreventing postoperative VTE [61], and as effectiveas unfractionated heparin or enoxaparin for thetreatment of VTE [6,62].Clinical trials are ongoingin patients with an ACS. Based on its molecularsize, fondaparinux might be expected to accumu-late in patients with renal insufficiency. However,there are two pieces of evidence suggesting theopposite is true. First, because fondaparinux istightly bound to antithrombin, animal studies have

Low-molecular-weight heparin in patients with chroric renal insufficiency 413

found that it is cleared along with antithrombin bythe liver, thereby bypassing renal clearance[63,64]. Second, in an analysis of the MatissePulmonary Embolism Study (fondaparinux vs.unfractionated heparin) database, the risk ofclinically important bleeding was similar in fonda-parinux-treated compared to heparin-treatedpatients (4.5% vs. 6.3%; P =NS), despite the factthat 52% of all patients had a GFR of 30—80 mL/min[6]. This finding implies that fondaparinux may notaccumulate in patients with renal insufficiency,since accumulation of fondaparinux would havebeen expected to result in an increased frequencyof bleeding. Regrettably, anti-Xa levels were notmeasured in this study to assess the potential foraccumulation in such patients.

Case presentation

You are called to see a 67-year-old man with type 2diabetes mellitus and end-stage renal failuresecondary to diabetic nephropathy who presentswith retrosternal chest pain and hypotension (bloodpressure 85/60 mmHg) one h into his usual hemo-dialysis session. Despite receiving 2 doses ofnitroglycerin 0.3 mg sublingually, the patient con-tinues to complain of chest pain, now ongoing for20 min. Review of the patient’s medical chartreveals a longstanding history of hypertension,dyslipidemia and a prior transient ischemic attack,with no prior history of cardiac disease or seriousbleeding. You note that his dry weight is 85 kg. Hiscurrent medications include aspirin, atorvastatindiltiazem and ramipril. On examination, he appearspale, with cool, clammy extremities. His bloodpressure has increased to 95/70 mmHg afterstopping hemodialysis, heart rate is 90 per minand regular respiratory rate is 25 per min andshallow, and he is afebrile. A 12-lead electrocar-diogram demonstrates 1—2 mm ST-segment depres-sion in the anterolateral leads. Cardiac troponin Ilevels are drawn, but are pending. You make aprovisional diagnosis of an ACS.

Q: What are the options for antithrom-botic management in this patient?

Antithrombotic therapies for non-ST elevation ACSinclude both antiplatelet and anticoagulant agents.Antiplatelet therapies, including aspirin, thieno-pyridines (ticlopidine, clopidogrel), glycoproteinIIb/IIIa inhibitors (abciximab, eptifibatide, tirofi-ban) will not be discussed in this review. Theanticoagulant management options include unfrac-

tionated heparin or LMWH. Most randomized trialshave examined combination therapy (unfractio-nated heparin and aspirin) and demonstrateddecreased death and recurrent myocardial infarc-tion (combined end points) with combination, asopposed to aspirin monotherapy. The optimal levelof anticoagulation with an ACS has not beenestablished, but available evidence supports aweight-adjusted dosing regimen when using unfrac-tionated heparin. An initial bolus of 60—70 U/kg(maximum 5000 U) and initial infusion of 12—15 U/kg/h (maximum 1000 IU/h) titrated to a targetactivated partial thromboplastin time (aPTT) of50—75 s is recommended [27]. In patients withnormal renal function, clinical trials using LMWHs(mainly enoxaparin, but also dalteparin and to alesser degree, nadroparin and tinzaparin) havegenerally shown decreased risk of death, recurrentangina and MI compared to unfractionated heparin,with equivalent or slightly decreased risk ofbleeding.

Most of these trials, however, did not adjustLMWH doses according to anti-Xa levels. Conse-quently, the level of LMWH anticoagulation that issafe and effective is uncertain. In the TIMI IIA study,a relationship between enoxaparin dose and hem-orrhagic complications was noted, particularlyamong those patients undergoing interventions(angiography, surgery, percutaneous coronary in-tervention). In those patients with major hemor-rhage, the anti-Xa levels ranged from 1.8 to 2.0 IU/mL. While this may provide estimates of the anti-Xarange for safety, the optimal level for efficacy isless certain. Based on animal studies, and non-randomized clinical studies of percutaneous coro-nary interventions, anti-Xa levelsN0.5 IU/mL resultin decreased rates of recurrent thrombosis. Conse-quently, anti-Xa levels ranging from 0.5 to 1.0 IU/mL measured 3—4 h following a subcutaneousinjection, likely provides adequate anticoagulationfor the management of an ACS and VTE, although itis acknowledged that this is based on littleevidence.

In this Case Presentation, use of LMWHs in thispatient is limited by the presence of end-stagerenal disease. While an initial therapeutic dose ofLMWH may be utilized, the subsequent doses andfrequency of dosing resulting in a safe level ofanticoagulation is unknown. Trough anti-Xa levels,drawn immediately prior to the next scheduleddose, could be utilized but interpretation of theseresults is not guided by evidence-based practiceand hence no recommendations can be made. Last,an important consideration in the anticoagulantmanagement is whether an interventional or non-interventional approach to the ACS management is

W. Lim et al.414

taken. In general, since the possibility of aninterventional strategy for ACS management can-not frequently be definitively determined at pre-sentation of an ACS, and because consistenttherapeutic anticoagulation has been demonstrat-ed to reduce mortality in ACS, our recommendationin the setting of end-stage renal disease failurewould consist of unfractionated heparin, as out-lined above.

In comparison to unfractionated heparin, rever-sal of the LMWH anticoagulant effect is unpredict-able using protamine sulfate. Animal and in vitrostudies have demonstrated that protamine neutra-lizes the antithrombin (anti-IIa) activity, but only60% of the anti-factor Xa activity of LMWHs [65].There are no available studies in humans whichhave supported or refuted a beneficial effect ofprotamine II on LMWH-induced bleeding.

Case presentation continued. . .

The patient’s symptoms resolve following the thirdadministration of nitroglycerine, and blood pres-sure increases to 120/75 mmHg. The electrocar-diogram returns to baseline, and troponin-I levelpeaks at 12.1 ng/dL. The patient is started onunfractionated heparin (bolus 5000 IU, and infusion1000 IU/h), and receives aspirin 160 mg orally,followed by 81 mg daily, and clopidogrel 300 mgorally, followed by 75 mg daily. Following assess-ment by the cardiologist, cardiac catheterization isscheduled within the next week.

Q: When should antithrombotic therapybe interrupted prior to interventionalprocedures in patients with renaalinsufficiency?

The presence of renal insufficiency does notinfluence the timing of discontinuation of antith-rombotic therapies. Unfractionated heparin is usu-ally discontinued 6 h prior to interventionalprocedures, with an aPTT level drawn prior to theprocedure to ensure no anticoagulant activity ispresent. For LMWHs, the dose immediately prior tothe procedure is usually held; hence, when admin-istered on a twice-daily, or once-daily basis, aminimum of 12 or 24 h occurs between the last doseand procedure, respectively. Anti-Xa levels are notroutinely measured prior to the procedure. Thie-nopyridines such as clopidogrel should be discon-tinued 5—7 days prior to cardiac surgery, and shouldnot be administered at presentation in patients in

whom diagnostic catheterization or bypass surgeryis anticipated within 5 days. There is currently noantidote to reverse the antiplatelet effects ofthienopyridines, and platelet transfusions may beindicated in patients who have received theseagents and experience bleeding symptoms.

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