Direct oral anticoagulants (DOAC) - Management of emergency situations. Rationale and design of the RADOA-Registry

Current specific anticoagulant reversal treatments are limited but include protamine to neutralise heparin and antithrombin-dependent low molecular weight-heparins (LMWH), and infusion of vitamin K to reverse the effects of vitamin K antagonists (VKA) (Levi, 2009).

More generic haemostatic agents, such as fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and recombinant factor VIIa (rVII), can be used to treat DOAC-taking patients who experience severe haemorrhage. However, evidence on their effectiveness for reversing DOACs is limited (Lauritzen et al., 2008; Bershad & Suarez, 2010).

An intensified effort to develop more specific antidotes for DOACs is ongoing and has achieved some success; with idarucizumab, a specific reversal agent or dabigatran, being the first of its kind to be approved for clinical use (EMA, 2015; FDA, 2015). More recently, the US Food and Drug Administration (FDA) approved the modified recombinant factor X protein, andexanet alfa in May 2018.  This antidote has been shown to reverse the anticoagulation effects of direct and indirect inhibitors of coagulation factor Xa and has been approved for the reversal of apixaban and rivaroxaban (Lu et al., 2013; FDA, 2018). A third specific antidote in development is ciraparantag; this synthetic small cationic and water-soluble molecule can bind to apixaban, rivaroxaban, edoxaban, and dabigatran, potentially achieving potent and rapid reversal of anticoagulation (Ansell et al., 2014).

Measuring the anticoagulant effects of DOACs in emergency situations

Routine monitoring of DOACs is not required (Burnett et al., 2016); however, measurements may be useful in emergency situations to potentially guide and optimise clinical management (Samuelson & Cuker, 2017).

While warfarin and phenprocoumon have a long half-life, meaning the international normalised ratio (INR) doesn’t vary widely from hour to hour and the timing of INR from last dose is not important (Tripodi, 2013), the relatively short half-life of DOACs makes the timing of the last dose important when performing coagulation assays. The peak concentration of DOACs are typically reached within 2–4 hours after oral intake, and half-lives of these drugs are usually 10–12 hours depending on renal and hepatic function. In patients with renal failure or if renal failure occurs, the half-lives of DOACs, and especially the renally eliminated dabigatran, can increase leading to accumulation and for the possibility of persistent bleeding - something that is often overlooked. Despite timing being key for DOAC coagulation assessment, currently there is no validated rapid quantitative point-of-care assay system for use during emergency situations, with satisfactory sensitivity and specificity to all DOACs (Sibbing & Spannagl, 2014).

There are a few measures currently being used, outlined in table 1, but they all come with their own challenges.

Table 1: Available measures of coagulation and their associated use and limitations

Management of life-threatening bleeding

When severe bleeding occurs, general assessment should include the following: evaluation of bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAID).

Gaining immediate reversal of antithrombic events is indicated in life-threatening bleeding events. One method of interrupting anticoagulation and reducing further exposure is through charcoal administration, although this is only useful when intake of DOAC was recent (<2–4 hours). Along with other methods of reversal and blood transfusions, the administration of PCC may be considered if specific antidotes are unavailable, although recommendations are based on expert opinion rather than clinical evidence (Aronis et al., 2016). Therefore, without further robust clinical data, the use of PCC (50 U/kg) should be used in patients with major, life-threatening bleeding (Escolar et al., 2015; Aronis et al., 2016).

Haemodialysis, which removes approximately 50% of dabigatran is another option. However, the limited use makes it impractical as it does not remove other DOACs, along with the associated bleeding risks and time to completion of treatment (Samuelson & Cuker, 2017).

Meanwhile, desmopressin, tranexamic acid, and ε-aminocaproic acid have unknown haemostatic efficacies in DOAC-associated bleeding (Siegal et al., 2014).

Management of emergency operations

The rise in patients taking DOACs is having a knock-on effect on the number of patients presenting to emergency departments requiring urgent surgery. When the need for emergency operation is identified, anticoagulation treatment should be discontinued, and supportive measures put in place. It is also recommended that spinal and epidural anaesthesia and lumbar puncture are avoided in these scenarios (Heidbuchel et al., 2015).

It is important to note that surgery can be scheduled 12–24 hours after last DOAC intake due to their short half-life. This is because the time of last intake and its residual concentration may have an influence on bleeding severity. Unfortunately, routine coagulation tests don’t provide much information except for aPTT in cases of dabigatran. As such, it is recommended that laboratory tests should include haemoglobin level, haematocrit, platelet count, renal function, and liver function (Kirchhof et al., 2016) and, more specific coagulation tests such as thrombin time or antiXa-assay where possible (Lindhoff-Last, 2017).

Frequently, the exact time of last intake might not be known, and delay of surgery may put the patient at greater risk. It is recommended that DOAC plasma concentrations should be <30 ng/ml for invasive procedures for operations to be performed without significantly increasing bleeding risk, although there is no prospective data available for this (Maegele et al., 2016). In cases where concentrations are above this threshold and surgery cannot be delayed, PCC and/or a specific antidote can be administered, although data on their effectiveness and safety before and during emergency operations is limited.

Management of head injuries in patients receiving DOAC treatment remains unclear, however, correction of haemostasis before initiating surgical treatment without increasing bleeding complications must remain the primary goal. In these cases, time is critical, and it is not possible to wait for laboratory results. Therefore, PCC (50 U/kg) and/or specific antidote should be administered as soon as possible prior to surgery (Maegele et al., 2016).

Levy et al., recently published recommendations outlining the scenarios where antidotes should be administered if DOAC-treated patients present with any of the following (Levy et al., 2016):

• life-threatening bleeding
• bleeding in a closed space or critical organ
• persistent major bleeding despite local haemostatic measures
• risk of recurrent bleeding due to delayed DOAC clearance or DOAC overdose
• urgent intervention that cannot be delayed and associated with a high risk of bleeding
• emergency surgery or intervention with a high risk of procedural bleeding

The RADOA-Registry (Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists)

To address the lack of data on outcomes following anticoagulation reversal, the RADOA-registry was established. This prospective non-interventional registry will evaluate the effects of both specific and non-specific reversal agents in patients with life-threatening bleeding or requiring emergency operations and who are receiving a DOAC or VKA.

By collecting case reports the registry aims to document the clinical course and outcome of various clinical bleeding events and urgent surgical interventions, characterise therapeutic strategies in stopping acute life-threatening bleeding, and analyse any left-over blood samples taken during the management of the acute event for drug concentrations and how that relates to outcomes.

The registry’s primary endpoint is the in-hospital mortality rate within 30 days of admission while a number of secondary endpoints have also been outlined including stopping of bleeding and bleeding control, fatality rate due to unstoppable bleeding, effectiveness of reversal agent use, delay in performance of surgery due to anticoagulation, and the relation of serious adverse events (SAE) to anticoagulation medication.

It is hoped that systematic analysis of these patients, along with the much-needed development of quantitative specific point of care test assays, will improve clinical management and promote favourable outcomes (Lindhoff-Last, 2017).