Prescribing DOACs with specific patient populations in mind

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

^{IMAGE: © KO STUDIOS}

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4 TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

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In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear