Treatment Failure in Patients Receiving Direct Oral Anticoagulants: Clinical Management and Outcomes from a Single-Center Review of 59 Consecutive Patients
Authors: McIlroy Graham , Smith Neil , Lokare Anand , Beale Karen , Kartsios Charalampos 
Published: October 2019

Abstract
Several direct oral anticoagulants (DOACs) have been developed that dose-dependently inhibit thrombin or activated factor X and offer potential advantages over vitamin K antagonists (VKAs), such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. DOACs have gained in popularity for the treatment and prevention of recurrence of venous thromboembolism (VTE), and the prevention of stroke/systemic embolism in patients with non-valvular atrial fibrillation (AF). However, the lack of routine monitoring means that their pharmacodynamic effect is rarely determined, leaving patients at potential risk of under- or over-anticoagulation. If adequately anticoagulated, the occurrence of thromboembolism (whether primary or recurrent) constitutes treatment failure; this has been reported in approximately 2% of patients in large DOAC clinical trials. The optimal management of such an event occurring with a DOAC remains unclear.
In this study, we sought to characterise DOAC treatment failures in our institution, and to rationalise the subsequent anticoagulation strategies in this setting. All VTE patients starting a DOAC at our centre are followed in a consultant-led clinic. Cases of suspected treatment failure are also referred from other specialities and primary care. Between September 2014 and May 2018, we identified 59 consecutive patients (male/female: 34/25) in whom a DOAC treatment failure was diagnosed, including non-resolution of the presenting complaint, and recurrence of or a new thrombotic event. Patient mean age at DOAC initiation was 56 (23-89) years. The median time from DOAC initiation to failure detection was 42 (3-1055) days. 36/59 (61%) patients were receiving a DOAC for treatment of acute VTE, while 19/59 (32%) patients were treated for the prevention of recurrent VTE and 4/59 (7%) patients were on a DOAC for atrial fibrillation. 4 (7%) patients had a thrombophilia background while 5 patients (8%) had an active cancer diagnosis.
On recognition of DOAC failure, 34 patients were on apixaban 5mg bd; 7 were on apixaban 2.5mg bd; 15 failed on rivaroxaban 20mg od; and 1 patient failed on each of rivaroxaban 10mg od, dabigatran 110 mg bd and edoxaban 30 mg od. All patients were compliant with their medication. For apixaban 5mg, the median time to failure was 29 (3-551) days; for apixaban 2.5mg it was 140 (26-441) days; for rivaroxaban it was 82 (20-1055) days. Two thirds of patients (39/59) were switched over to therapeutic low-molecular-weight heparin (LMWH), 6/59 patients (10%) were initiated to warfarin with appropriate LMWH bridging, and 11/59 patients (19%) were switched to an alternative DOAC. 3 patients (5%) continued their existing anticoagulant. Most patients (33/39, 85%) initially switched to LMWH following a median time on parenteral anticoagulation of 57 (14-472) days were subsequently switched to oral anticoagulants: 18% to warfarin, 82% to a DOAC. By the end of follow-up, 37/59 patients (63%) were taking a DOAC, including 8 patients who had been switched back to the anticoagulation regimen that failed at the outset, and a further 4 patients returned to the same drug at a higher dose. Of the remainder, 8 patients (14%) were taking a VKA, 8 patients (14%) remained on LMWH, 1 patient was on aspirin and 5 patients (8%) had stopped their anticoagulation treatment. A diagnosis of post-thrombotic leg was made in 15/36 (42%) patients with acute lower limb VTE who failed their DOAC.
There is currently a lack of guidance on how to manage patients who fail initial treatment with a DOAC. To the best of our knowledge our study is the first to record the clinical experience in this challenging patient group. Based on our findings, a common strategy is to switch to therapeutic LMWH. After a successful period of parenteral therapy, most patients were switched back to oral treatment, typically another DOAC. Still this did not seem to prevent post-thrombotic syndrome in 42% of patients who were initially diagnosed with acute lower limb thrombosis.
Treatment failure is a recognised risk of nearly all medical therapies including DOACs. It is therefore not surprising to encounter such patients in day-to-day practice. The growth in the number of anticoagulant choices has made it more difficult to know how to respond when one fails. As the use of DOACs continues to expand, this problem - and the need for an evidence-based solution - is likely to grow.

Disclosures
Smith: BMS: Honoraria, Speakers Bureau. Beale:Daiichi Sankyo: Speakers Bureau. Kartsios:Bayer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Boehringer Inglelheim: Consultancy, Honoraria, Speakers Bureau.