Unfractionated Heparin Dosing in Obesity for Thromboprophylaxis: A Literature Review

It has been well established that venous thromboembolism (VTE) risk is higher in patients with obesity and that standard thromboprophylaxis doses are possibly subtherapeutic.1 Guidelines on VTE prophylaxis state further research is needed on weight based dose adjustments in extreme body weights and offer no recommendations as of yet for the best dosing strategy.  Weight based dose adjustments in LMWH was originally studied in bariatric surgery patients with enoxaparin 40 mg twice daily in patients with a BMI <50 and 60 mg twice daily in a BMI >50 to yield a reduction in VTE rates with minimal bleed risk. 2-3 Further studies in other patient populations have supported weight-based LMWH regimens in obese patients; though, doses considered were broad and have not demonstrated a clear correlation with VTE or bleed risk and anti-FXa activity. Studied doses of enoxaparin ranged from 0.4-0.5 mg/kg daily to twice daily.4-6  In unfractionated heparin (UFH), useful in patients with poor renal function or when shorter lasting anti-coagulation is needed, pharmacokinetic data for UFH suggests obese patients may require doses greater than the standard dose (5,000 units every 8-12 hours) though the optimal dose remains unclear.  A review was conducted of recent literature to attempt answering the question: does high dose UFH in patients with obesity or morbid obesity improve VTE prevention without increasing bleed risk?  Three observational studies were found that attempted to address this question and are reviewed here.

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One retrospective cohort study published in 2014 identified VTE and bleed events in hospitalized patients weighing more than 100 kg that were started on  either high dose thromboprophylaxis (unfractionated heparin 7,000 units three times daily or enoxaparin 40 mg twice daily) or standard dose thromboprophylaxis (unfractionated heparin 5,000 units two-three times daily or enoxaparin 40 mg once daily).7 Results of this study included 9,241 patients and found a higher rate of thromboembolisms in the standard dose group (1.52% vs 1.18%, p=0.22) with a subgroup analysis revealing those with a BMI >40 having a significant difference in VTE rates (1.48% vs 0.77%, p=0.05). In the secondary analysis, this study did not find an increased bleed risk associated with the higher dose of thromboprophylaxis; therefore, the authors concluded that in morbidly obese hospitalized adults, the higher dose thromboprophylaxis halved the VTE risk without increasing bleed risk (VTE OR 0.52; 95% 0.27-1.00, p=0.05; bleed OR 0.84, 95% CI 0.66-1.07, p=0.15; ARR 0.71%, NNT 140).  While this study was internally validated and found a slight benefit in higher dose thromboprophylaxis therapy in morbidly obese patients, the ultimate effect of heparin versus enoxaparin was not differentiated, nor was dosing frequency in the standard dose group (two versus three times daily), and the secondary analysis of bleed risk was not powered to detect a potential difference.

Another retrospective cohort study published in 2016 considered VTE and bleed rates in hospitalized patients that were >100 kg and received either high dose (n=751) or standard dose (n=584) unfractionated heparin (7,500 units or 5,000 units every eight hours).8  Results were further sub-analyzed based on BMI classes (overweight: 25-29.9 kg/m2, class 1: 30-34.9 kg/m2, class 2: 35-39.9 kg/m2, class 3: >40 kg/m2) with notable baseline characteristic differences in the BMI class 3- high dose heparin group, including less major surgeries, more extensive medical history, concurrent antiplatelet use, and higher body weight (versus class 3- low dose heparin group: 147 +/- 31 kg vs 135 +/- 25 kg, p <0.01).  Contrary to the previous study, results from this one found thromboembolism rates greater in the high dose heparin group (high dose vs low dose:  VTE 3% vs 1.5% p=0.14) with no notable differences observed between BMI classes.  Bleed rates were also higher amongst the high dose heparin group while being statistically significant, with the greatest difference seen between the BMI classes 2 and 3 (all patients: high dose 10% versus low dose 7%, p <0.01 bleed defined as >2g/dL Hgb drop in 24-hour period).  A multi-variable logistic regression analysis on the BMI class 3 patients specifically found high dose heparin associated with bleeds (high dose 71% vs low dose 52%, OR 3.4, 95% CI 1.58-7.42, p<0.01). From these results, the authors conclude that high dose prophylactic heparin in patients >100 kg was not associated with a decreased VTE risk but was associated with an increased bleed risk.  These results support continuing standard dosing with the presumption that higher doses only increase bleed risk without adding VTE protection though contradictory to other studies that show potential benefit.  The baseline characteristics may skew these results but this study suggests a potential subtle difference between the obesity sub-classes and bleed risk when using high dose UFH. 

One other retrospective cohort study published in 2018 compared VTE and bleed rates between patients with BMI >30 kg/m2 (n=1673) or <30 kg/m2 (n=3437) that were started on unfractionated heparin 5,000 units every 8 hours for VTE prophylaxis during hospitalization.9 This study further sub-analyzed obese patients based on the same BMI classes as previous studied and found a comparable VTE rate between both groups and all BMI sub-classes (0.6% vs 0.7%, p= 0.70).  Additional sub-group analysis found patients in the ICU to have higher VTE rates than non-ICU patients (1.8% vs 0.2%, p<0.001) but no difference between patients weighing >100 kg versus <100 kg (0.6% vs 0.7%, p=0.73).  Propensity scoring analysis revealed a poor association between obesity and VTE occurrence (OR: 1.4, 95% CI 0.7-3.0, p =0.39), thus leading the authors to conclude that standard heparin dosing is appropriate in obese patients.  Reported bleed events were found to be comparable between the two study groups (intracranial hemorrhage 0.1% vs 0.2%, p = 0.34, GI bleed 0.4% vs 0.4%, p>0.99). This study, while small and retrospective, appears to be powered appropriately and suggests that standard dosing in patients that are obese may be adequate for VTE prophylactic though is discordant to the first study reviewed. 

This review of available literature regarding the appropriateness of high dose UFH in patients with obesity for VTE prophylaxis revealed clinical data is sparse and conflicting, consisting of moderate to low-quality evidence.  One review article published in 2016,10 proposed UFH 7,500 units three times daily may be appropriate, citing the first article reviewed here despite results being reported as a composite of both anticoagulants and conflicting with the two later studies. This conundrum of missing and conflicting data has left room for discussion and professional judgement; with a common, conservative option being continuing standard dosing while erring on the “every 8 hours” regimen versus “every 12 hours.” Rationale behind this, in addition to adhering to FDA approved dosing for UFH, includes the utility of UFH 5,000-unit vials without needing to draw-up partial vials (e.g. 1 ½ vials for each dose), thus minimizing opportunity for dosing errors and medication waste.  This seems reasonable given the current data that is inconclusive.

1. Schünemann HF, Cushman M, Burnett AE, et. all (2018). American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Advances; 2(22): 3198-3225.
2. Borkgren-Okonek MF, Hart RW, Pantano JE, et all (2008). Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity. Surg Obes Relat Dis; 4 (5): 625-31.
3. Bartlett MA, Mauck KF, Daniels PR (2015). Prevention of venous thromboembolism in patients undergoing bariatric surgery. Vascular Health & Risk Management, 11: 461–477.
4. Freeman AL, Pendelton RC, Rondina MT (2010). Prevention of venous thromboembolism in obesity. Expert Rev Cardiovasc Ther; 8(12): 1711–1721.
5. Ludwig KP, Simons HJ, Mone M, et all (2011). Implementation of an Enoxaparin Protocol for Venous Thromboembolism Prophylaxis in Obese Surgical Intensive Care Unit Patients. Annals of Pharmacotherapy, 45: 1356-62.
6. Willett, KC, Alsharhan M, Durand C, Cooper MR (2013).  Dosing of enoxaparin for venous thromboembolism prophylaxis in obese patients. Annals of Pharmacotherapy; 41(12): 1717-20.
7. Wang, T, Milligan PE, Wong, CA, et all (2014). Efficacy and safety of high dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost; 111(1):88-93.
8. Joy M, Tharp E, Hartman H, et all (2016). Safety and Efficacy of High Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients.  Pharmacotherapy; 36(7):740-748.
9. Patanwala AE, Seaman SM, Kopp BJ, Erstad BL (2018).  Heparin dosing for venous thromboembolism prophylaxis in obese hospitalized patients: An observation study.  Thrombosis Research; 169: 159-156. 
10. Vandiver JW, Ritz LI, Lalama JT (2016). Chemical prophylaxis to prevent venous thromboembolism in morbid obesity: literature review and dosing recommendations.  J Thromb Thrombolysis; 41:475-81.

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