Underdosing in obesity-an epidemic: Focus on anticoagulation

    Obesity is a growing problem in the United States. Currently, 68% of adult Americans are overweight (BMI >25 kg/m²).¹ Of those, 35% are obese (BMI >30 kg/m²) and 6% are morbidly obese (BMI >40 kg/m²).^1-2 It is estimated that by 2030, 51% of the population will be obese and 11% will be morbidly obese.¹   We are often confronted with dosing drugs in an obese patient. Unfortunately, many clinical trials exclude or have limited overweight patients enrolled; thus, optimal dosing for both safety and efficacy in this population is lacking. Pharmacokinetic studies in obese patients have shown that the volumes of distribution of lipophilic drugs and the clearance of hydrophilic drugs can be increased.^3–4 For this reason, dosing in obesity should be patient- and drug-specific.     

Obese patients are often initiated on anticoagulation for venous thromboembolism (VTE) prophylaxis, VTE treatment, or acute coronary syndrome (ACS) treatment. Concerns for bleeding in obese patients have raised the question of whether dose adjustments or dose capping is necessary. Unfractionated heparin (UFH) has a nonlinear pharmacokinetic profile and is not distributed into adipose tissue.⁴ Studies have shown that total body weight (TBW) is the most important predictor of anticoagulation requirements.^5–7 However, physicians are often cautious of abnormally high doses of UFH. One retrospective study found that based on recommended dosing guidelines, only 10% of obese patients received the correct bolus dose and only 25% were initiated on the correct infusion dose. The gap between the recommended dose and prescribed dose amplified as body weight increased.⁸ Since the adoption of TBW UFH protocols, numerous studies have been undertaken to determine optimal dosing in obese patients. Multiple studies have supported the use of TBW dosing protocols for obese patients.^9,10 However, some studies found that using TBW, morbidly obese patients required smaller infusion rates or experienced greater aPTT values compared to their controls.^11–14

Low-molecular-weight heparins (LMWHs) are predominantly concentrated in the plasma with little distribution into adipose tissue.¹⁵ Guidelines offer little guidance except suggesting anti-Xa monitoring with subsequent dose adjustments in obese patients.¹⁶ Focusing on treatment dosing, some studies have compared anti-Xa levels based on weight in obese and non-obese patients and determined that dose adjustments may not be necessary.¹⁷ Bazinet et al found that when utilizing weight-based dosing of enoxaparin without dose capping there was no difference in subtherapeutic, therapeutic, or supratherapeutic levels among patients treated for atrial fibrillation (AF), ACS, or VTE.¹⁸ Data from trials have not confirmed increased bleeding in obese patients. Al-Yaseen et al found rates of bleeding with dalteparin to be consistent with those previously reported, without significant alterations in anti-Xa levels.¹⁹ A retrospective review found no difference in the rate of major hemorrhage between obese and non-obese patients with ACS.²⁰ The Computerized Registry of Patients with Venous Thromboembolism (RIETE) suggested no significant difference in recurrent VTE between obese (>100 kg) and non-obese patients treated with LMWH. Doses may have been capped; therefore, strong conclusions cannot be drawn.²¹ Pooled results suggest that to ensure adequate anticoagulation, treatment doses of UFH and LMWH should be based on TBW without capping. Due to conflicting results, special consideration and close monitoring should be taken into account when dosing morbidly obese patients with UFH. Anti-Xa monitoring may be appropriate for obese patients on LMWH therapy especially those weighing > 190 kg as data is particularly lacking in these patients.²²

Concerns also exist with underdosing UFH and LMWH for VTE prophylaxis since obesity itself is a risk factor for the development of VTE in the hospitalized medical patient.²³ Guidelines suggest that obese surgical patients or patients undergoing bariatric surgery may require higher prophylactic doses.²⁴ Strategies such as increasing the fixed dose or administering a TBW-based dose have been studied. A study looking at morbidly obese patients found that heparin 7,500 units 3 times daily or enoxaparin 40 mg twice daily decreased VTE occurrence by 50% compared to standard prophylactic regimens.²⁵ A subgroup analysis showed that compared to placebo, fixed-dose dalteparin was equally effective in non-obese and obese patients; however, no benefit was seen in patients with a BMI >40 kg/m².²⁶ Scholten et al compared higher than normal fixed-dosing strategies (enoxaparin 30 mg or 40 mg twice daily) in bariatric surgery patients. Results showed a decrease in VTE utilizing 40 mg twice daily without an increase in major bleeding.²⁷ A retrospective analysis found that enoxaparin 0.5 mg/kg twice daily was effective at maintaining prophylactic anti-Xa levels without increasing major bleeds.²⁸ Based on results of clinical trials, standard fixed doses of LMWH and UFH may not provide adequate VTE prophylaxis in obese patients. Trials have demonstrated that various dosing strategies providing higher doses of LMWH and UFH may be necessary.

Warfarin has been the only oral anticoagulant on the market in the United States for over 50 years. Numerous factors have been identified that affect warfarin dose requirements; however, the effects of obesity have not been established. One retrospective review found that when initiated in hospitalized patients, obese and morbidly obese patients with therapeutic INRs had higher average daily warfarin discharge doses than normal-weight patients; 6.7 mg, 6.7 mg, and 4.4 mg, respectively. Increased time to a therapeutic INR was also noted between normal-weight (6 days), obese (8 days), and morbidly obese patients (10 days). The obese and morbidly obese patients were significantly younger, which could affect the results as elderly patients frequently have lower warfarin requirements.²⁹

The recent addition of an oral direct thrombin inhibitor and two Xa-inhibitors expands our oral anticoagulation options. Unfortunately, studies focusing on dosing in obesity are lacking. Dabigatran is approved in the United States for prevention of stroke and systemic embolism in nonvalvular AF.³⁰ The RE-LY trial noted a 20% decrease in trough concentrations in patients weighing >100 kg; however, dose adjustments have not been recommended.³¹ Although not approved for VTE prophylaxis in the US, a post-hoc analysis compared dabigatran to enoxaparin 40 mg once daily for prevention of VTE in orthopedic surgery patients. No significant difference was noted in the composite endpoint of major VTE; however, the comparator dose of enoxaparin may be inappropriate for obese patients.³²

Rivaroxaban is approved for prevention of stroke and systemic embolism in nonvalvular AF, DVT and pulmonary embolism (PE) treatment and reduction of recurrence, and DVT prophylaxis after knee and hip surgery.³³ A phase 2 study demonstrated that a TBW >120 kg was not associated with clinically significant changes in pharmacokinetic or pharmacodynamics parameters; thus, dose adjustments are not warranted.³⁴ Studies with rivaroxaban have a small proportion of patients with a BMI of >28 kg/m² or weights exceeding >100 kg; however, subgroup analyses have shown dose modifications are not needed.^35–37

Apixaban is the most recent agent to be approved for prevention of stroke and systemic embolism in nonvalvular AF.³⁸  One study found that a 10-mg dose of apixaban yielded a 20% decrease in peak concentration in patients weighing >120 kg. The authors concluded that these alterations were not clinically significant and no dose alteration is needed.³⁹ The ARISTOTLE trial reported weights as greater than or less than 60 kg, so efficacy in obesity cannot be assumed.⁴⁰ Although the manufacturers of apixaban state dose adjustment for obese patients is not warranted, the subanalysis of ARISTOTLE has not been published.

As the obesity epidemic continues to affect Americans, we struggle with ensuring adequate therapeutic drug concentrations of anticoagulants while balancing the increased risk of bleeding. Data on appropriate dosing of anticoagulants in obese patients is limited. Dosing of these medications should be based on patient- and drug-specific factors.

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Dr Buehler is assistant professor of pharmacy practice, department of pharmacy practice, St. Louis College of Pharmacy, St. Louis; and Dr Yancey is associate professor of pharmacy practice, department of pharmacy practice, St. Louis College of Pharmacy, St. Louis. 

Disclosure information: The authors report no financial disclosures aas related to products discussed in this article.