Clinical Investigations: Acute Ischemic Heart Disease
Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes*

https://doi.org/10.1067/mhj.2002.120774Get rights and content

Abstract

Background The current standard of care for patients with non-ST-segment elevation acute coronary syndromes (ACS) includes antithrombotic therapy with aspirin and heparin. Although emerging data suggest that low-molecular weight preparations offer distinct advantages over unfractionated heparin, limited information on patient-related factors that may influence dosing, safety, and efficacy is available. Purpose The purpose of our study was the determination of the impact of patient age, sex, body weight, and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in patients with ACS. Methods and Results Patients enrolled in the TIMI 11A trial received a full complement of antiischemic therapy, aspirin, and enoxaparin (30 mg intravenously, followed by weight-adjusted doses of either 1 mg/kg or 1.25 mg/kg subcutaneously every 12 hours). Before and after the third and last doses, blood samples were obtained from 445 patients for measurement of anti-Xa activity. The mean apparent clearance, distribution volume, and plasma half-life were 0.733 L/h, 5.24 L, and 5 hours, respectively. Among a wide range of clinical and laboratory covariates, creatinine clearance emerged as the most influential factor on apparent clearance, area under the curve, and anti-Xa activity. Patients with marked renal impairment (creatinine clearance <40 mL/min) had higher trough and peak anti-Xa activity compared with those with normal renal function and were more likely to have major hemorrhagic events. Conclusion The pharmacokinetic and pharmacodynamic profiles after enoxaparin administration are consistent across a broad range of patients with ACS. Dose adjustments or anti-Xa coagulation monitoring or both will be necessary rarely in routine clinical practice, with the exception of patients with severe renal insufficiency. (Am Heart J 2002;143:753-9.)

Section snippets

Methods

The TIMI 11A study, a multicenter dose-ranging trial to evaluate the safety of enoxaparin (Lovenox, Aventis Pharmaceuticals, Bridgewater, NJ) in the treatment of patients with non-ST-segment elevation ACS, has been published previously.11 In brief, patients initially received a full complement of antiischemic medications (β-blocker, nitrate, calcium channel antagonist) and a 30-mg intravenous bolus of enoxaparin, followed immediately by weight-adjusted (actual) doses of either 1 mg/kg or 1.25

Baseline characteristics

Blood samples were obtained from 445 patients with unstable angina and non-ST-segment elevation myocardial infarction for anti-Xa determination. The baseline characteristics for the overall study population and according to creatinine clearance are summarized in Table I.

. Baseline characteristics of patients enrolled in the TIMI 11A anti-Xa substudy according to creatinine clearance (mL/min)

Empty CellAll patients (n = 445)Creatinine clearance <40 (n = 11)Creatinine clearance 40-80 (n = 149)Creatinine

Discussion

The emergence of encouraging data derived from large-scale, randomized clinical trials,15, 16, 17, 18 coupled with several attractive features including ease of administration and excellent bioavailability, are responsible for the acceptance of LMWH as standard treatment among patients with venous and, more recently, arterial thrombotic disorders.19, 20, 21 Although fixed (1.0 mg/kg) weight-adjusted dosing is appropriate for most patients with ACS, our findings suggest that, in contrast to

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    *

    Reprint requests: Richard C. Becker, MD, Director, Cardiovascular Thrombosis Research Center, University of Massachusetts Medical School, Worcester, MA 01655.

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