A 2021 analysis evaluated patient characteristics and clinical settings where direct oral anticoagulant (DOAC) treatment failure manifests. A total of 51 manuscripts describing 79 patients who exhibited DOAC failure were included for analysis. Patients were more commonly male (51.6%), with a mean age of 52.8 years (range 18 to 88 years). The most common treatment failures were determined to be in patients with antiphospholipid syndrome (APS; 44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). Higher failure rates were also observed for rivaroxaban (65.8%), followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). The most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19%), and deep vein thrombosis (19%). Based on this analysis, the authors determined that DOACs have the potential to fail, even in the setting of Food and Drug Administration (FDA) and non-FDA-approved indications. It should be noted that this analysis is strictly based on case reports, and as such, the findings are subject to confounding factors and may vary in clinical practice. [1]
The authors discussed potential mechanisms for failure, thought to be most likely explained by pharmacokinetic and pharmacodynamic properties. Lower failure rates of apixaban and edoxaban may be related to dosing and half-life; rivaroxaban for example has a half-life of 9-13 hours, although it is prescribed at a dose of 20 mg once daily after an initial dosing regimen of 15 mg twice daily. Its relatively fast elimination rate, and high, early peaks of the drug may result in increased risk of bleeding and low troughs, resulting in potentially inadequate anticoagulation. Conversely, apixaban and dabigatran are dosed twice daily with half-lives ranging from 12-17 hours, resulting in a more stable plasma concentration and predictable efficacy. Regarding dabigatran, differences in absorption may be yet another factor contributing to increased risk of failure. The prodrug of dabigatran exhibits limited bioavailability, with stomach and intestinal absorption easily hindered by the lack of acidic conditions. These environmental conditions may be affected by proton pump inhibitors and liver metabolism, for example. Furthermore, DOACs are renally eliminated; elevated renal clearance may decrease efficacy due to rapid elimination, while reduced renal clearance may result in increased risk of bleeding. [1]
Drug-drug interactions may also be a potential culprit, as DOACs are CYP3A4 and P-glycoprotein substrates. Many case reports identified within this review (n= 13 patients) documented patients with concomitant use of a strong CYP inducer, enhancing clearance of the DOAC. Finally, noncompliance with even a single dose of DOAC may be more substantial due to their relatively short half-life, compared to vitamin-K antagonists (VKA), for example, which have a half-life of several days. In the event of a missed VKA dose, the extended half-life allows for a more continuous effect. Alternatively, missing a single dose of a DOAC can lead to inadequate anticoagulation. Notably, many cases of failure documented herein (n= 14) utilized DOAC therapy for APS, an off-label use not supported by robust randomized trials that may complicate ideal drug selection. Among all the cases, some also indicated success when switching to a different DOAC, as reported in 6 cases, with 4 switches being successful due to use of a DOAC with a different mode of action and/or different pharmacokinetic/pharmacodynamic properties. Ultimately, selection of DOAC should be individualized based on patients’ clinical profiles to minimize risk of failure. [1]
A 2020 review discussing common clinical challenges with use of DOACs indicates comorbidities that may affect DOAC pharmacokinetics include renal insufficiency, hepatic impairment, and extreme body weights due to their potential to alter the DOAC elimination rate and increase the risk of thromboembolic or bleeding events. All DOACs therapies are eliminated by the kidneys to varying degrees, and thus, alterations in renal clearance must be taken into account when dosing these agents. Dabigatran is the most renally eliminated (80%), followed by edoxaban (50%), rivaroxaban (35%), apixaban (27%), and betrixaban (11%). Due to the variation in DOAC levels that may occur in patients with renal impairment, it is important to renally dose DOACs appropriately as recent studies suggest that up to 32% of patients experience inappropriate DOAC dosing, with the most common form being subtherapeutic dosing due to renal insufficiency. Inappropriate dosing of DOACs can carry consequences, including increased risk for thrombotic and bleeding complications resulting from subtherapeutic and supratherapeutic dosing, respectively. [2]
Similar to patients with renal impairment, patients with hepatic impairment are also at increased risk of bleeding complications and thrombotic events during DOAC administration, as alterations in hepatic function affect DOAC biotransformation to varying extents. Apixaban is the most reliant on hepatic metabolism for drug elimination, accounting for 75% of its elimination pathway, followed by rivaroxaban (65%), edoxaban (50%), dabigatran (20%), and betrixaban (18%). As there is no proficient monitoring parameter to assess for safety, patients with hepatic dysfunction may not be ideal candidates for DOACs. All DOACs can be considered in patients with mild hepatic impairment without any dose adjustment, but with lack of available data, the optimal anticoagulation strategy for this patient population remains unclear. [2]
As for patients with hepatic impairment, optimal anticoagulation strategy and DOAC dosing have not been established for patients with extreme body weights. Recently, concerns have arisen that use of DOACs in patients with extreme body weight may be impacted by physiological changes that affect clearance of the medication, leading to adverse outcomes and limited data to guide prescribers. Based on pharmacokinetic changes, fixed DOAC doses may lead to decreased drug exposures in obese patients and increased drug exposures in underweight patients. Despite subgroup analyses and meta-analyses of data from DOAC clinical trials revealing no difference in efficacy or safety outcomes in obese patients, extreme-body-weight populations have been underrepresented in clinical trials. An analysis conducted by the International Society on Thrombosis and Haemostasis (ISTH) suggests that DOACs are safe in patients ≤ 120 kg at standard doses but are not recommended in patients > 120 kg. [2]
Patients with low body weight (<60 kg) also represent a population in which measuring renal function plays a vital role in assessing use of DOACs, as renal function is commonly overestimated due to lower muscle mass. Low-body-weight patients typically present with comorbid conditions that predispose them to adverse outcomes (i.e., elderly age, frailty, and renal impairment). Overall, pharmacokinetic data suggest extreme body weights affect DOAC disposition, but published data has not adequately confirmed this. While the patient populations mentioned within this review have not explicitly observed increased DOAC failure rates, the complexity of therapeutic management and DOAC dosing in these patients, potentially leading to altered levels, presents potential situations in which DOAC failure may be more likely to occur. [2]
Another 2020 review provides additional insight into certain special populations where DOAC efficacy may become altered. As gastrointestinal surgery alters the absorptive surface, DOAC drug absorption may be affected, leading to greater variability in anticoagulant drug levels. However, the evidence for use in this population is noted to be extremely limited. Bariatric surgery or extensive bowel surgery may also directly alter anticoagulant levels. Additional studies have also observed inter-individual differences between patients despite receiving the same DOAC regimen. These findings are concerning, as DOAC level assessment is not commonly performed. Even if abnormal absorption is identified, individual-based dosing of DOACs is not commonly practiced. [3]