Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?

Timing of Off-Label Dosing of Direct Oral Anticoagulants in Three Large Health Systems

Direct oral anticoagulants (DOACs) were shown to provide safe and effective anticoagulation in patients with atrial fibrillation (AF) and venous thromboembolism (VTE). These drugs strongly changed the management of anticoagulated patients because, at variance to the treatment with vitamin K antagonists (VKAs), they do not require regular laboratory monitoring and are used in fixed dosages, allowing great simplification of the treatment. However, all the marketed DOACs are available in two dosages, a standard and a reduced dose, each indicated for patients with specific clinical characteristics. When DOACs are used for the prevention of stroke in AF, dosage should be adapted according to the patient's clinical characteristics that have been clearly defined for each drug.[1] Instead, when DOACs are used for patients with acute VTE, only the standard dose is indicated, with the exception of edoxaban.[2] [3] When DOACs are used in VTE patients for late secondary prevention, a low dose of apixaban or rivaroxaban is indicated.[4] [5] Though these drugs allowed an undoubtedly simplified management of anticoagulation compared with VKAs, the use of DOACs requires a good knowledge of the different indications and dosages.[1] [3] However, several studies indicate that inadequate dose prescription is frequently found in clinical practice, with a high prevalence of underdosing, especially in AF patients who do not meet dose reduction criteria.[6] [7] [8] [9] [10] [11] Instead, few data are available on the use of inappropriate DOAC dosage among VTE patients,[12] and these data suggest a higher rate of bleeding, recurrent VTE, and death among undertreated patients. Reasons for underdosing are mainly related to advanced age, moderate-to-severe renal failure, female sex, and low body weight.[6] Moreover, a reduced dose is also suggested when a potentially interfering drug is associated with DOACs,[13] and co-medication could be a reason for inadequate dosing. As a consequence of the high frequency of underdosing in AF patients found in clinical practice, a major concern was raised that inadequate anticoagulation could lead to high stroke risk.[14] On the contrary, a reduced bleeding risk was reasonably expected in patients who receive low-intensity anticoagulation.

In the current issue of the journal, Herron et al[15] published a study aimed to identify whether off-label DOAC dosing is occurring in AF and VTE patients and evaluate the effectiveness of prescribing oversight using a registry-based intervention, leading to putting the off-label prescriptions to the attention of the provider and possibly to correct dosage. The authors have reported the results of the Michigan Anticoagulation Quality Improvement Initiative (MAQI[2]) registry, which was regularly reviewed by specifically trained abstractors to evaluate the appropriateness of dose prescription. The Register was integrated with the Food and Drug Administration (FDA) indications for optimal DOACs dosage use. The system generates “DOSE alerts” when patients are prescribed off-label DOACs doses that do not align with prescribing guidelines. Trained data abstractors respond to the DOSE alerts and either resolve the alert or contact the site investigator when indicated, to determine what intervention may be needed. The contacted prescriber may decide to change the anticoagulant, change the dose, discontinue an interacting drug, or make other adjustments. Over 5 years, a total of 569 dose alerts were generated for AF patients and 162 dose alerts were generated for VTE patients. Interestingly, the greatest number of alerts occurred for both AF and VTE patients, in the first year of observation, then a low rate of alerts was found in the following years, suggesting that the surveillance is associated with increased adherence to dose recommendations. Alerts led to contact the prescriber in 19.3% of cases among AF patients, and 14.8% among VTE patients. For both AF and VTE patients, the contact led to modifying the prescription in approximately 75% of cases. The results of the study support the conclusion that DOACs prescribing oversight are effective in identifying and correcting errors, reducing off-label DOACs use, and possibly increasing the safety of the treatment. The study was underpowered to give results on the impact of the intervention on outcomes.

In approaching DOACs' adequate dose prescription, it is necessary to clearly separate DOACs treatment in relation to the indication for anticoagulation, because the landscape of VTE patients is completely different from that of AF patients. When anticoagulation is required for acute the VTE, there is an urgent need to obtain adequate and rapid anticoagulant effect, therefore DOACs dosages in this context should be strictly used at recommended doses. Instead, when DOACs are used for stroke prevention in AF patients, a high prevalence of off-label DOACs dosage use was found. Inappropriate overdosing is a less frequent finding, and it is reported in 1.3 to 6.5% depending on the DOACs considered in the Global Anticoagulant Registry in the Field - Atrial Fibrillation (GARFIELD-AF) study[6] and 0.3% in Survey on anTicoagulated pAtients RegisTer - Atrial Fibrillation (START-AF) Registry.[11] Notwithstanding the low frequency of overdosing, this inappropriate prescription may expose patients to higher bleeding risk. On the contrary, underdosing is quite a frequent finding but, when the outcome of underdosed patients is analyzed, unexpected results are found. Recent meta-analysis[16] [17] of published studies found no different risk of stroke/Transient ischemic attack (TIA) and cardiovascular events among patients who were inappropriately underdosed, and similar results were confirmed more recently in the START-AF Registry.[11] Different and conflicting results have been reported with respect to the bleeding risk. Data from the GARFIELD-AF Study showed a significantly lower risk of bleeding.[6] However, no increase in the safety profile was found by some studies[10] [11] and subsequently confirmed.[14] [15] Instead, published results agree in reporting that the mortality rate was always higher among undertreated patients.[6] [10] [11] [14] [16] Though current rules for dose adjustment take into account the patient clinical characteristics that are associated with frailty, such as increased age, renal failure, and low body weight, they seem not sufficiently sensible to identify patients at high risk for mortality, and physicians probably prefer to adopt in clinical practice more precautional prescriptions, independently from the rules defined by international guidelines. The high frequency of underdosing has been reported in different countries and the large diffusion of this practice should raise questions on the reasons that are behind this frequent prescribing behavior. Dose prescription rules have been established based on the results of the randomized clinical trials (RCTs) leading to the approval of DOACs use. However, these trials were conducted more than 10 years ago, when the enrolled population of AF patients was substantially different from the current clinical practice. The RCTs comparing warfarin with DOACs published between 2009 and 2013, enrolled AF patients with a median age ranging from 70 to 73 years.[18] During the recent years, a progressive increase in the median age of patients undergoing anticoagulation has been recorded.[11] [19] [20] According to the increased age, an increased number of comorbidities and an increase in co-medications is expected among these patients. The definition of “appropriate dosage” established on data from the registration trials, probably does not fulfill the current characteristics of AF patients. In addition, data from studies conducted with laboratory measurements of DOACs' concentrations give us other suggestions. Even though DOACs do not require laboratory measurement, when DOACs' concentrations have been measured a wide interindividual variability has been reported.[21] [22] [23] These variability in plasma concentrations of DOACs is enhanced in elderly patients, and this behavior is present also in patients on DOACs reduced dose, with a relevant impact on the anticoagulation levels.[24] The results of the recently published Measure and See Study—MAS Study—confirmed a relation between low anticoagulant levels and thrombotic complications on the one hand, and high anticoagulant levels and bleeding risk on the other hand.[25] [26] Moreover, in this study a group of patients showed high DOAC activity levels associated with high bleeding risk, despite they were treated with low-dose DOACs. The results of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation (ELDERCARE) study[27] [28] suggest the possible use of dosages different from the approved ones. More than 10 years after the marketing of these drugs, adequate DOACs use in AF patients has probably not been completely investigated. Further studies, to explore the potential therapeutic effect of DOACs and a better treatment tailoring for stroke prevention in AF are needed.

Conflict of Interest

None declared.

• References

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Publication History

Received: 14 October 2024

Accepted: 15 October 2024

Article published online:
12 November 2024