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Balancing Safety and Efficacy with Anticoagulants: Where Are We Now? by M. Cardinalea The direct oral anticoagulants (DOACs) represent a major advancement for patients requiring oral anticoagulant therapy. Use of these agents is rapidly expanding due to randomized controlled trials demonstrating improved efficacy and similar or decreased bleeding rates compared to warfarin. This rapid increase in utilization highlights the importance of ensuring appropriate patient, agent, and dose selection when prescribing these high-risk medications. This article will discuss the role of DOACs in several special populations that may be particularly sensitive to inappropriate use, and the outcomes that may be associated with off-label dosing of DOACs.
Introduction In 2016, 17.6% of all ED visits for outpatient adverse drug effects were associated with anticoagulants, more than any other class of drugs.1 Of these, almost 50% resulted in hospitalization.1 As the superior efficacy and ease of use of the DOACs lead to greater patient exposure to these agents, caution should be used when prescribing these high-risk medications to ensure appropriate patient selection and dosing according to the labeling.
Key Points • DOACs are increasingly preferred over warfarin due to their attractive safety and efficacy. • Certain special populations require careful consideration when selecting a DOAC for anticoagulation. • Surgical patients receiving oral anticoagulant therapy represent a unique challenge for clinicians and require special consideration. • One in eight patients receiving a DOAC agent may be receiving an inappropriate dose based on the package insert, and this may be associated with poor outcomes. 16
Commentary The ease of use of the DOACs has the potential to result in overuse of these agents. Patient-specific factors that influence the potential risks or benefits of DOAC therapy must be considered with selecting an oral anticoagulant. For example, in elderly patients apixaban seems to exhibit the safest profile most consistently, and dabigatran seems to increase gastrointestinal bleeding risks.2,3 Unfortunately, however, all of the available data in the elderly population is limited to indirect comparisons from meta-analysis or observational data, making it difficult to draw solid conclusions.2,3 If a DOAC is used in these vulnerable patients, renal function should be monitored very closely, and the DOAC should be discontinued if severe renal impairment occurs. In patients with renal impairment, care should be exercised when selecting the correct dose according to indication. For rivaroxaban and dabigatran, it should be noted that the creatinine clearance calculation is performed using actual body weight. The reliance of drug elimination on the kidney should also be taken into account, as 80% of dabigatran is eliminated unchanged by the kidney, compared to 27% of apixaban. In patients undergoing hemodialysis, dosing should be based on the package insert or these drugs should be avoided, since a large study on patients in a dialysis database demonstrated higher bleeding rates when unadjusted doses of dabigatran or rivaroxaban were used.4 In patients with morbid obesity defined as a BMI >40 kg/m2 or body weight > 120 kg, DOACs should be avoided until more data is available.5 If they are used, calibrated anti-Xa assay monitoring should be performed to ensure therapeutic levels are within an expected level.5 However, these assays are currently not readily available. Lastly, more studies are needed to characterize the role of DOACs in patients with malignancy. In the treatment of venous thromboembolism associated with cancer, low molecular weight heparin (LMWH) should be offered first, and DOACs can be used if LMWH is refused.6 In patients on DOACs requiring surgical intervention, careful consideration should be made to determine the risk of interrupting anticoagulation therapy in relation to the risk of bleeding based on both patient-specific factors and surgery-