Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes

Abstract

BackgroundPhase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non-ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been repor ted to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations. AimThe aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside. MethodsThirty-eight patients, median age 78 years (range 44-87), mean GFR 32 ml min -1 (range 16-117) and mean weight 69 kg (range 32-95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti-Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen. ResultsThree hundred and thirteen anti-Xa concentrations were collected. A two compar tment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (V c ). The fraction of drug excreted unchanged ( F u ) was estimated at 71%. CL and V c from the final covariate model were estimated as; CL (l h -1 ) = 0.681 per 4.8 l hr -1 (GFR) + 0.229 V c (l) = 5.22 per 80 kg (total body weight) Correspondence Bruce Green,

Treatment with Dalteparin is Associated with a Lower Risk of Bleeding Compared to Treatment with Unfractionated Heparin in Patients with Renal Insufficiency

“…4,5 Because LMWHs are primarily excreted by the kidney, there is concern for bioaccumulation of LMWHs in patients with chronic renal insufficiency receiving repeated doses, in particular with the hydrophilic enoxaparin. 6 However, given the varying molecular and pharmacokinetic features of the LMWHs, results found with one type of LMWH are not necessary applicable to other LMWHs. Sigueret, Pautas, and their group showed that there was no accumulation of anti-factor Xa activity over a 10-day treatment period of therapeutic tinzaparin, and in a subsequent study conducted over 30 days, reported the absence of correlation between anti-Xa levels and creatinine clearance with therapeutic tinzaparin therapy.…”

Enoxaparin Outcomes in Patients With Moderate Renal Impairment

“…The large-scale clinical studies instrumental in the approval of current dosing enrolled healthier patient populations than those seen in everyday clinical practice and often excluded patients with renal dysfunction. Smaller studies 7,[15][16][17] have made dose modifications to target an antifactor Xa activity therapeutic range, despite a lack of strong evidence correlating antifactor Xa activity target range to outcomes. 18,19 Thus, we conducted a review of medical records to compare the outcomes of bleeding and recurrent thrombotic events in patients with normal renal function vs those with moderate renal impairment who were receiving the manufacturer's recommended therapeutic dose of enoxaparin.…”

“…Considering the impact of major bleeding as an adverse drug event that may include life-threatening or fatal hemorrhage, we suggest that regulatory agencies, the manufacturer, and/or guidelinewriting organizations explore all available data, published and unpublished, and consider revising dosing and/or monitoring guidelines in patients with moderate renal impairment. Others 7,15,17 have offered alternative dosing strategies and, although use has been investigated in a limited number of patients, these regimens merit consideration ( Table 5).…”

“…14 The mechanism responsible for increased bleeding in patients with reduced renal function appears to be increased anticoagulant effect secondary to drug accumulation. Studies [5][6][7]9,15,17,33 evaluating enoxaparin pharmacokinetics via antifactor Xa activity have consistently shown increased drug half-life and accumulation of antifactor Xa activity in patients with moderate renal impairment. The consensus of these studies is that dose adjustment is necessary to avoid drug accumulation.…”

Risk Factors for Bleeding Events with Enoxaparin, Dabigatran and Fondaparinux in Hospitalized Patients with Varying Levels of Renal Impairment

“…Moreover, a study by Green et al suggested that enoxaparin accumulation occurs after steady state is achieved in patients with CrCl ≤ 80 ml/min. This accumulation is especially prominent in the moderate renal impairment range; hence, the authors recommend an empiric dose adjustment based on pharmacokinetic and pharmacodynamic data [16]. However, the package insert only recommends dose reduction at a CrCl<30 ml/min.…”