Prospective comparison of three enoxaparin dosing regimens to achieve target anti‐factor Xa levels in hospitalized, medically ill patients with extreme obesity

Enoxaparin is commonly used to prevent venous thromboembolism (VTE) 1, 2 but has not been well-studied in patients with extreme obesity, a population at high risk for VTE. We prospectively compared three enoxaparin dosing regimens for the achievement of goal peak anti-Factor Xa levels in medically ill patients (n = 31) with extreme obesity (body mass index (BMI) ≥ 40 kg/m2). Patients were assigned to receive fixed-dose (FD) enoxaparin 40 mg daily (QDay,n = 11), weight-based, lower-dose (LD) enoxaparin 0.4 mg/kg QDay (n = 9), or weight-based, higher-dose (HD) enoxaparin 0.5 mg/kg QDay (n = 11). The average BMI and weight of the entire cohort was 62.1 kg/m2 (range 40.5–82.4) and 176 kg (range 115–256 kg) and did not differ between groups. Peak anti-Factor Xa levels were significantly higher in the HD group compared to either LD or FD groups. Patients in the HD group achieved target anti-Factor Xa levels more frequently than the LD and FD groups (P 40 kg/m2), a major risk factor for VTE 1, 5, 6, were under-represented in VTE prophylaxis trials of enoxaparin (40 mg once daily (QDay)) in medically ill patients 3, 7. Obesity affects drug distribution and kinetics 1, 2, 8. For example, in obese patients given FD enoxaparin 40 mg QDay anti-Factor Xa activity and actual body weight are inversely correlated 9, 10 and higher rates of VTE prophylaxis failure have been reported 11. Although ACCP practice guidelines suggest increasing the dose of pharmacologic agents such as enoxaparin for the prevention of VTE in obese patients 4, optimal dose adjustments remain unclear. Given the striking rise in the prevalence of extreme obesity 12, 13, understanding how to best adjust the dose of enoxaparin in these patients is crucial in order to optimally prevent VTE in this high-risk population. We prospectively enrolled hospitalized, consenting, medically ill patients at risk for VTE (n = 31) with extreme obesity (BMI ≥ 40 kg/m2). Patients were sequentially assigned to one of three enoxaparin dosing groups, matched for age, weight, and BMI. The first was a control group who received FD enoxaparin 40 mg daily (QDay, n = 11), the current FDA approved dose of enoxaparin for the prevention of deep vein thrombosis in medically ill patients. Groups 2 and 3 were intervention groups assigned to either weight-based LD enoxaparin 0.4 mg/kg QDay (n = 9) or weight-based HD enoxaparin 0.5 mg/kg QDay (n = 11). All patients had anti-Factor Xa levels drawn upon study enrollment and then daily, during their hospital stay, when feasible. Our primary outcome was the achievement of target peak anti-Factor Xa levels (defined as a peak anti-Factor Xa level between 0.2 and 0.5 IU/mL, measured 4–6 hr after enoxaparin administration). The three groups were well matched on the pre-specified variables of age, weight, and BMI (Table I). The average BMI exceeded 60 kg/m2 in all three groups, consistent with our goal of recruiting patients with extreme obesity. The average weight exceeded 170 kg in all three groups (range 115–256 kg) and the maximum weights were 254 kg, 238 kg, and 256 kg for the FD, LD, and HD groups, respectively (Table I, P = NS). There was no difference in the time between enoxaparin administration and measurement of peak anti-Factor Xa levels between the three groups (Table I). In addition to obesity, the most common VTE risk factors were sepsis (n = 20/31, 64.5%) and acute respiratory failure (n = 12/31, 38.7%). Overall, almost half of our subjects (n = 15/31, 48.4%) had ≥2 major VTE risk factors (excluding the risk factor of morbid obesity). The primary outcome (anti-Factor Xa level between 0.20 and 0.50 IU/mL 2, 14) was achieved significantly more often in the HD group compared to either the FD or LD group (Fig. 1 ). Patients in the LD group achieved target anti-Factor Xa levels more often than the FD group but remained inferior to the HD group (Fig. 1). Furthermore, 82% of patients in the FD group had anti-Factor Xa levels 20 days) hospitalization due to transfer to the intensive care unit or operating room and subsequent surgical service following study enrollment. Patients were not followed following hospital discharge or transfer. Overall, a total of 38 peak anti-Factor Xa levels in the LD and HD groups (on average, 1.9 anti-Xa levels per patient) were measured. This reflects the median length of stay of 3 days in these patients and includes 15 and 23 anti-Factor Xa measurements in the LD and HD groups, respectively. Only one anti-Factor Xa level was obtained in the FD group, as they represented a control group. Peak anti-Factor Xa levels in the HD group were significantly higher than levels in the FD and LD groups (Fig. 2). Although anti-Factor Xa levels trended higher in LD group compared to the FD group, differences did not reach statistical significance (Fig. 2). In stepwise, multiple regression analyses peak anti-Factor Xa levels were not correlated with any of the pre-specified variables of age, actual body weight, BMI, time (enoxaparin dose administration to anti-Factor Xa measurement), gender, or estimated creatinine clearance (based on the method of Cockroft and Gault, using adjusted body weight 15-17). Consistent with published data 18, 19, peak anti-Factor Xa levels were higher with repeated enoxaparin dosing, although the overall increase was not significant(enoxaparin dosing Day 1: 0.23 (0.17, 0.34); enoxaparin dosing Day 2: 0.28 (0.20, 0.36); enoxaparin dosing Day 3: 0.28 (0.20, 0.31), P = 0.69. Patients in the HD group were significantly more likely to achieve a goal anti-Factor Xa level on enoxaparin dosing Day 2 compared to patients in the LD group (100% versus 25%, P 60 kg/m2 is superior to both FDA-approved fixed enoxaparin dosing (40 mg QDay) and LD weight-adjusted enoxaparin (0.4 mg/kg QDay) for the achievement of target peak anti-Factor Xa levels (between 0.2 and 0.5 IU/mL). These data support studies in both medically ill and surgical patients 1, 9, 11, 17 and are consistent with ACCP practice guidelines 4 suggesting that higher doses of pharmacologic thromboprophylaxis should be considered in patients with obesity. In the current study, we extend these published observations by prospectively comparing three enoxaparin dosing regimens in medically ill patients with extreme obesity. By enrolling patients with an average BMI and weight exceeding 60 kg/m2 and 170 kg, respectively, our findings provide new evidence of the predictability of weight-based enoxaparin (0.5 mg/kg QDay) for DVT prophylaxis in patients weighing up to 256 kg. The findings of the current study also suggest that enoxaparin 0.5 mg/kg effectively achieved recommended anti-Factor Xa levels without an observed increase in bleeding or thrombosis complications, although our study was not powered to determine clinical efficacy or safety. Similarly, a dosing regimen of enoxaparin 0.5 mg/kg did not result in therapeutic levels of anti-coagulation. The primary limitations of the current study are the small sample size and the lack of clinical outcomes associated with the anti-Factor Xa measurements. A large, multicenter clinical trial is obviously necessary in order to demonstrate reductions in thrombotic events with a weight-based enoxaparin dosing algorithm for VTE prophylaxis. Nevertheless, until those clinical trials are completed, these data provide new pharmacokinetic evidence of the benefit of enoxaparin 0.5 mg/kg over FD enoxaparin in patients with morbid obesity. Differences between groups were large enough that despite the small sample size, the absolute magnitude of difference in peak anti-Factor Xa levels between FD and HD enoxaparin (Fig. 2) was sufficient to provide 99.9% power to avoid a Type II error (using a two-sided, α =0.05). Although the creatinine clearance was significantly lower in patients who received FD enoxaparin, there was no correlation between anti-Factor Xa levels and creatinine clearance and thus we do not believe this difference confounded our results. We also did not enroll any patients with a creatinine clearance 70, heart failure, acute respiratory failure, previous VTE, cancer, stroke, sepsis, and immobility (defined as ≥3 days of bed-rest) 4. Patients were excluded if they were pregnant, on therapeutic anticoagulation, had a bleeding disorder, platelet count of less than 100,000/mL, coagulopathy, active bleeding, estimated creatinine clearance <30 mL/min (based on the method of Cockcroft and Gault using adjusted body weight 15-17), or stroke, surgery, or trauma within 14 days. This study was approved by the institutional Ethics Committee on human research and all patients provided informed consent. Patients were consecutively identified and assigned sequentially to one of three groups. The first was a control group assigned to FD enoxaparin 40 mg daily (QDay, n = 11). Groups 2 and 3 were intervention groups assigned to either weight-based LD enoxaparin 0.4 mg/kg QDay (n = 9) or weight-based HD enoxaparin 0.5 mg/kg QDay (n = 11) in random fashion. Peak anti-Factor Xa levels were measured daily, 4–6 hr after the enoxaparin dose for up to three days in patients assigned to either LD or HD groups, while patients remained hospitalized on a medicine service. For safety, when patients were transferred to the ICU, a surgical team, or a non-medicine service, VTE prophylaxis was chosen at the discretion of the primary team. Our primary outcome was the achievement of target peak anti-Factor Xa levels (defined as a peak anti-Factor Xa level between 0.2 and 0.5 IU/mL, measured 4–6 hr after enoxaparin administration). Enoxaparin dosing for the HD group was based on previous studies in medically ill obese patients 17. Enoxaparin dosing for the LD group was chosen with consideration of published investigations 17, 22. We estimated that the average weight of enrolled patients in the current study would be 150 kg. A weight-based enoxaparin dose of 0.4 mg/kg would provide a conservative 50% dose increase on average over fixed-dosing (e.g., 40 mg daily). This dosing also was chosen to allow comparisons of safety and efficacy between a more moderate (e.g., 0.4 mg/kg) and more aggressive (e.g., 0.5 mg/kg) prophylactic dosing regimen. Our study protocol specified that patients would have Group 1 (n = 11) received FD enoxaparin 40 mg once daily (QDay), Group 2 (n = 9) received LD enoxaparin 0.4 mg/kg QDay, and Group 3 (n = 11) received HD enoxaparin 0.5 mg/kg QDay. Actual body weight was determined upon hospital admission with a standardized, calibrated scale. The dose of enoxaparin was not capped and was rounded to the nearest 5 mg unit in accordance with standard procedures to ensure the precise administration of each dose, as we have done previously 17. Medication administration times were reconciled with laboratory records to ensure the precise capture of the interval between enoxaparin dosing and peak anti-Factor Xa level measurements. No patients received other types of heparinoids during the study period that would have interfered with anti-Factor Xa measurements. Patients were monitored daily during their hospitalization with routine clinical laboratory tests (e.g., complete blood count) and clinical assessments for the development of any adverse events such as symptomatic VTE (including DVT and PE), major or non-major clinically significant bleeding (defined as fatal bleeding, bleeding resulting in the transfusion of ≥ 2 units of packed red blood cells, bleeding in a critical site, such as intracranial hemorrhage, retroperitoneal bleeding, or bleeding that required medical intervention (e.g., gastrointestinal bleeding requiring endoscopy, epistaxis requiring nasal packing, etc), and thrombocytopenia concerning for HIT in accordance with current guidelines23). Peak anti-Factor Xa levels were obtained through venipuncture 4–6 hr after the dose of enoxaparin was given, as described before 17 and briefly reviewed here. A pilot tube was drawn first and an exact ratio of 9 volumes of blood to 1 volume of anticoagulant (32 g/L citrate) was maintained. The Rotachrom® assay using the STA-Compact instrument (Diagnostica Stago, Parsippany, NJ) was used to quantify anti-Factor Xa (LMWH) activity for enoxaparin. Thesensitivity of this assay is 0.2 U/mL and within run imprecision is 5.5 (% CV) at 1 U/mL. The assay is linear between 0.2 and 2.0 U/mL. All anti-Factor Xa levels were analyzed by technicians blinded to the assigned treatment regimen. The target range for peak anti-Factor Xa levels was chosen to be 0.2–0.5 IU/mL 14. The sample size for this pilot study was chosen to provide a cohort large enough to identify differences between groups, based on previous studies 17. Descriptive statistics were used to calculate summary data. Data are represented as the mean ± SD, unless otherwise indicated. For all analyses, continuous variables were assessed for normality visually and with skewness and kurtosis tests (version 11.0, StataCorp, College Station, TX 77845). Parametric, two-tailed t-tests or ANOVA were used for continuous variables and the chi-square and Fisher's exact test for categorical variables with a predetermined alpha level of P < 0.05. Stepwise, multiple regression analyses were used to identify any pre-specified variables potentially affecting peak anti-Factor Xa levels, including age, actual body weight, BMI, time (enoxaparin dose administration to anti-Factor Xa measurements), gender, or estimated creatinine clearance. Authors thank all the patients that agreed to participate in this study, Ms. Pam Proctor and Linda Kelly for their research oversight, Dr. Chris Lehman for his assistance with anti-Factor Xa measurements, and Diana Lim for her assistance with illustrations and tables. Andrew Freeman*, Tuesdy Horner , Robert C. Pendleton*, Matthew T. Rondina* , * Department of Internal Medicine, University of Utah, Salt Lake City, Utah, Department of Pharmacy, Presbyterian Hospital, Albuquerque, New Mexico, Molecular Medicine, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah