FAQ
Low-molecular weight heparin for the treatment of thromboembolism in obese patients
Patients may require oral anticoagulation for various reasons including the treatment or prevention of thromboembolic disease, including deep vein thrombosis (DVT) or pulmonary embolism (PE), for the prevention of embolic stroke in patients with atrial fibrillation or mechanical heart valves, or the prevention of recurrent events in patients with a history of acute myocardial infarction (MI). In the event that such patients require an invasive intervention such as surgery, dental procedures or colonoscopy with potential polypectomy, their oral anticoagulation, usually warfarin, will need to be discontinued for several days prior to the procedure to allow their coagulation status to return to baseline. Under such circumstances, these patients, especially those at high risk, including patients with valve prostheses, recent (within 3 months) thromboembolism, and high risk atrial fibrillation, will require “bridging” with either unfractionated heparin (UFH) or a low molecular weight heparin (LMWH). The decision of whether or not to “bridge” these patients rests on the inherent risks of both thromboembolic and bleeding complications.
Both UFH and LMWH are effective in this setting. Because of its short half-life, the effects of UFH can be quickly reversed prior to a procedure by discontinuing the infusion, however, its administration requires hospitalization and frequent monitoring. LMWH, on the other hand, does not require hospitalization or intensive monitoring in most cases. Several studies have shown that LMWH provides therapeutic levels more rapidly and consistently than UFH. Current CHEST guidelines (The 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy) recommend that for patients at high risk for thromboembolism warfarin be stopped about 5 days prior to the procedure to allow the INR to normalize and that full dose UFH or LMWH therapy should be started about 2 days prior to the procedure as the INR falls to normal. UFH should be stopped 4 hours prior to the procedure to allow the anticoagulant effect to dissipate. LMWH should be discontinued 20 to 25 hours (last dose the morning the day before surgery) prior to the procedure to allow its anticoagulant effect to diminish or wear off.
Because of its convenient administration and more consistent therapeutic profile, LMWH has become a popular alternative to UFH in the setting of anticoagulation bridging; however, its use and dosing remain problematic in obese patients.
Nearly one-third of adults in the United States are obese (Body Mass Index (BMI) of ≥ 30), and the prevalence of obesity in the U.S. more than doubled from 1960 to 2004 and continues to rise. As the population of obese patients continues to rise, so will the demand for the use of LMWH in these patients; however, weight based dosing presents a potential problem for prescribers. The package inserts for enoxaparin, dalteparin, and tinzaparin recommend a dose of 1 mg/kg subcutaneously (SC) every 12 hours, 200 IU/kg SC once daily (maximum 18,000 IU per day), and 175 IU/kg once daily based on total body weight, respectively. Body surface area and total body weight are better predictors of anti-factor Xa levels than are lean body weight and ideal body weight. Many clinicians prefer to cap LMWH doses out of concern for over-anticoagulation and the risk for bleeding events; however, there is also concern that the capping of doses in morbidly obese patients may result in under-dosing of these patients and under-anticoagulation.
Some studies have evaluated the use of dalteparin and enoxaparin in obese patients. A study by Yee and Duffull 2000 looked at 20 patients (10 obese and 10 of normal weight) who were matched for age, gender and lean body weight, and all had normal renal function who were treated with dalteparin for DVT, PE or unstable angina (UA). Patients received 200 IU/kg/day for DVT or 120 IU/kg twice daily for PE or UA. Obese patients were dosed based on lean body weight (LBW), adjusted body weight (ABW) or total body weight (TBW) depending on the clinician preference; a correction factor of 0.4 was used to calculate adjusted body weight. The mean TBW in the obese group was 106.4 (± 22.1) kg vs. 69.7 (± 9.3) kg in the normal weight group. This study found that there was a significant correlation between anti-factor Xa levels and TBW as well as ABW, which supports the dosing of dalteparin in obese patients based on TBW or ABW rather than LBW.
An additional study by Wilson and colleagues stratified 37 patients into 3 weight groups: those within 20% of their ideal body weight (IBW), N = 13, those within 20% to 40% of IBW, N = 14, and those > 40% over their IBW, N = 10. Patient weights ranged from 56 kg to 190 kg. Patients received dalteparin 200 IU/kg SC once daily based on TBW for a minimum of 5 days, and peak anti-factor Xa levels were checked 3 to 4 hours after the day 3 injection, while trough levels were checked prior to doses on days 3 and 5. Both peak and trough levels were similar across all patient groups indicating that once daily weight-based dosing without a dosing cap is appropriate in moderately obese patients for the usual 5-day duration of bridging. No patients experienced hemorrhagic or thromboembolic complications either during LMWH therapy or at 90-day follow-up. These findings suggest TBW is preferred for dosing dalteparin in obese patients.
A retrospective review of 193 patients weighing > 90 kg who received dalteparin for the treatment of DVT or PE was conducted by Al-Yaseen and colleagues. Patients included in this study had a mean weight of 114.2 (± 18.3) kg and ranged from 91 to 182 kg. Of the 193 patients included in the study, 151 patients (78%) received the recommended daily dose of 200 IU/kg within ± 5% of dalteparin for 5 to 7 days based on TBW. There were no major bleeds within 2 weeks of diagnosis; however, 2 patients experienced a major bleed, one at 4 weeks post-diagnosis and the other at 8 weeks post-diagnosis which resulted in a bleeding rate of 1% (95% confidence interval (CI) 0.1 to 3.7). This bleeding rate is similar to other previously reported rates. Three patients experience a recurrent thromboembolism (one PE at 2 weeks post-diagnosis and 2 DVTs at 11 weeks post-diagnosis), yielding a recurrence rate of 1.6% (95% CI 0.3 to 4.5) at 3 months.
Sanderink and colleagues conducted a randomized, open-label, crossover study involving obese and non-obese volunteers. The BMI of the obese subjects was 30 to 40 kg/m2 and the weight range for the obese group was 78 to 144 kg. Enoxaparin 1.5 mg/kg based on TBW SC daily for 4 days was given or 1.5 mg/kg as a single 6-hour IV infusion. The washout period was 7 days between regimens. Anti-Xa activity and pharmacokinetic parameters were evaluated. Pharmacokinetic analysis of the SC dosing revealed that obese subjects had a higher area under the curve (AUC) compared to non-obese subjects (difference at day 4, 19%, p=0.002). The only other significant difference was a delayed time to maximum concentration (Tmax) in obese subjects (1-hour delay on day 4, P<0.01). The maximum anti-Xa activity was similar between groups. Analysis of the IV dosing pharmacokinetics revealed a lower total clearance and volume of distribution for obese subjects when the parameters were adjusted for weight. Again, anti-factor Xa levels were similar. Overall, weight-adjusted SC dosing of enoxaparin yielded slightly higher anti-factor Xa levels in obese subjects compared to non-obese subjects, and although its absorption is complete in both groups, its Tmax was delayed by about 1 hour in obese patients. The authors concluded that there does not appear to be a reason to adjust the dose for obese patients.
Based on the data presented here, low-molecular-weight heparins appear to be safe and effective in obese patients up to 190 kg (the highest weight included in these studies); although, overall, few patients in these studies weighed over 150 kg. When dosing LMWH in these patients, actual body weight should be used rather than lean body weight or ideal body weight. The practice of dose capping does not appear to be justified in these patients. The decision of whether or not to use LMWH in obese patients should be individualized to the specific patient in question, given the relatively small pool of data available, especially in patients weighing more than 150 kg. If the decision is made to use LMWH in these patients, twice daily dosing may be considered over once daily dosing based on data that suggest subtherapeutic anti-factor Xa levels are more common in patients who received once-daily LMWH than those who received twice daily dosing. Until more data are available, especially in patients over 150 kg, it may be prudent to monitor anti-factor Xa levels when using LMWH in this patient population or to use UFH.
References
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008:133(6 suppl):160S–198S.
Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008:133 (6 suppl):299S–339S.
George-Philips KL, Bungard TJ. Use of low-molecular-weight heparin to bridge therapy in obese patients and in patients with renal dysfunction. Pharmacotherapy. 2006;26(10):1479-1490.
National Institute of Diabetes and Digestive and Kidney Diseases: Weight-control Information Network. Statistics Related to Overweight and Obesity. http://win.niddk.nih.gov/statistics/. Updated May 2007. Accessed June 16, 2008.
Lovenox [package insert]. Bridgewater, NJ: Sanofi-aventis; 2007.
Fragmin [package insert]. New York, NY: Pfizer Incorporated; 2007.
Innohep [package insert]. Thornhill, Ontario, Canada: LEO Pharma Incorporated; 2003.
Yee JYV, Duffull SB. The effect of body weight on dalteparin pharmacokinetics: a preliminary study. Eur J Clin Pharmacol. 2000;56(4):293-297.
Wilson JS, Wilbur K, Burton E, Anderson DR. Effect of patient weight on the anticoagulant response to adjusted therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism. Haemostasis. 2001;31(1):42-48.
Al-Yaseen E, Wells PS, Anderson J, Martin J, Kovacs MJ. The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients. J Thromb Haemost. 2005;3(1):100-102.
Sanderink GJ, Le Liboux AL, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72(3):308-318.
Smith J, Canton M. Weight based administration of dalteparin in obese patients. Am J Health-Syst Pharm. 2003;60(7):683-687.
Bazinet A, Almanric D, Brunet C, et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 2005;116(1):41-50.