A Protocol for the Use of Enoxaparin During Pregnancy: Results from 85 Pregnancies Including 13 Multiple Gestation Pregnancies

Huxtable, Lindsay M.; Tafreshi, Mohammad J.; Ondreyco, Sharon M.

doi:10.1177/107602960501100206

Cited by 20 publications

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“…Still, the frequency of antifactor Xa monitoring in pregnancy has not been well described, and there are no established recommendations. Although limited reports show inconsistent results on the necessity of antifactor Xa monitoring, [22][23][24] our results suggest that if the desired targets 9 are to be achieved, antifactor Xa monitoring may be desirable. In our practice, we found that monthly antifactor Xa levels were reasonable to assess the need for dosage adjustments; additional information in the future may obviate the need for such frequent testing.…”

Section: Discussionmentioning

confidence: 69%

Dosing and Monitoring of Low‐Molecular‐Weight Heparin in High‐Risk Pregnancy: Single‐Center Experience

et al. 2011

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Study Objective To evaluate dosing requirements and monitoring patterns of LMWH when used in high-risk pregnancy. Design A retrospective observational cohort study Setting University of Illinois at Chicago Medical Center Patients Those treated with LMWH from 2001 – 2005 for either prophylaxis or treatment of VTE during pregnancy and monitored with anti-factor Xa activity. Main Results Data was obtained on 53 pregnancies in 49 women. Mean starting doses (mg) and doses most proximate to delivery of twice daily enoxaparin were, for prophylaxis and therapeutic groups, respectively, 39.2 (range 30–60) and 55.0 (range 30–100), p = 0.06; and 83.0 (range 30–180) and 85.7 (range 30–160), p = 0.41. Weight-based mean starting doses (mg/kg) and doses most proximate to delivery were 0.46 vs. 0.62 (p =0.03), and 0.90 vs. 0.87 (p=0.29), for prophylaxis and therapeutic groups, respectively. Dose changes were required in 9/13 (69.2%) and 21/38 (55.2%) patients in the prophylaxis and therapeutic groups, respectively to achieve target anti-Factor Xa activity. The weight-based prophylactic dose was consistently 0.6 mg/kg in all three trimesters achieving a target anti-Factor Xa activity of 0.39 ± 0.18 IU/ml, while the therapeutic dose was 0.9 mg/kg to maintain anti-Factor Xa activity of 0.71 ± 0.22 IU/ml. Conclusion Dose changes for LMWH throughout pregnancy as guided by anti-Factor Xa activity were common. A significant increase in the LMWH dose requirements in the prophylactic group suggests that more frequent monitoring of anti-Factor Xa activity may be appropriate in pregnant patients to maintain target anticoagulant levels.

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Section: Discussionmentioning

confidence: 69%

Dosing and Monitoring of Low‐Molecular‐Weight Heparin in High‐Risk Pregnancy: Single‐Center Experience

et al. 2011

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“…Following successful use of unfractionated heparin in pregnant women during the 1970's and 1980's [Hirsh et al, 1970;Bonnar, 1976;Spearing et al, 1978;Anon (c), 1979;de Swiet et al, 1980;Bonnar, 1981;Chen et al, 1984;Letsky and de Swiet, 1984], as LMWH therapy gained acceptance in antenatal practice through the 1990's, a number of groups began publishing research or information on the pharmacokinetics and use of different LMWH during pregnancy [Priollet et al, 1986;Melissari et al, 1992;Gillis et al, 1992;Sturridge et al, 1994;Hunt et al, 1997;Nelson-Piercy et al, 1997;Blomback et al, 1998;Casele et al, 1999;Brennard et al, 1999;Bremme et al, 2000;Ellison et al, 2000;Crowther et al, 2000;Leqercq et al, 2001;Rodie et al, 2002;Hunt et al, 2003;Jacobsen et al, 2003;Sephton et al, 2003;Norris et al, 2004;Smith et al, 2004;Ensom et al, 2004;Huxtable et al, 2005;Fox et al, 2008;Lebaudy et al, 2008;Ni Ainle et al, 2008;Simpson et al, 2009;Friedrich et al, 2010] (see table 1.10 for a summary of each study). Case report of a patient with a massive ileo-femerol DVT managed with once daily adjusted dose enoxaparin (60-80mg daily) from week 13 of her pregnancy.…”

Section: Pharmacokinetic Studies Of Lmwh During Pregnancymentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Patel

Green

Patel

et al. 2012

Blood

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503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

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“…10 The evidence for increasing the total daily dose or dosing frequency during pregnancy is based on small, historical, observational studies. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] Prescribing a twice-daily dosing regimen of LMWH has significant implications for women with respect to injection burden, particularly if the VTE event occurs early during pregnancy.…”

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confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

et al. 2013

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Background-The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results-Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance.Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twentythree patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once-versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once-and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. Conclusions-The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered. Patel et al Population PK of Enoxaparin During Pregnancy 1463of Obstetricians and Gynaecologists (RCOG) guidelines for the management of antenatal VTE suggest a twice-daily dose of enoxaparin or dalteparin, 9 whereas the American College of Chest Physicians guidelines state that a once-or twice-daily dose could be used, acknowledging the uncertainty that exists around the optimal LMWH dosing regimen for this indication. 10 The evidence for increasing the total daily dose or dosing frequency during pregnancy is based on small, historical, observational studies.11-27 Prescribing a twice-daily dosing regimen of LMWH has significant implications for women with respect to injection burden, particularly if the VTE event occurs early during pregnancy. Clinical Perspective on p 1469We developed a population pharmacokinetic model 28 to better understand the specific pharmacokinetic changes in LMWH during pregnancy and, through pharmacokinetic simulation, determined the optimal dosing strategy to use during pregnancy for the treatment of antenatal VTE. MethodsPregnant women ≥18 years of age who were referred to the specialist thrombophilia clinic at King's College Hospital were eligible for recruitment to the study. King's Co...

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A Protocol for the Use of Enoxaparin During Pregnancy: Results from 85 Pregnancies Including 13 Multiple Gestation Pregnancies

Cited by 20 publications

References 24 publications

Dosing and Monitoring of Low‐Molecular‐Weight Heparin in High‐Risk Pregnancy: Single‐Center Experience

Dosing and Monitoring of Low‐Molecular‐Weight Heparin in High‐Risk Pregnancy: Single‐Center Experience

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

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