In Case of Emergency: Don’t Rely on ‘Normal’ Range Assays With DOACs

(UPDATED) The rising popularity of direct oral anticoagulants (DOACs) for patients requiring long-term anticoagulation poses a quandary in medical emergencies such as ischemic and hemorrhagic stroke. Namely, how do you assess a patient’s anticoagulation level prior to thrombolysis or urgent surgery?

“This is a big deal,” Larry Goldstein, MD (University of Kentucky, Lexington), told TCTMD. “When a patient comes in with an acute stroke, one of the contraindications to using intravenous tPA is folks who are therapeutically anticoagulated. For folks who were on warfarin, that was relatively easy.”

Back when warfarin was the main anticoagulant in use, a simple INR test was all that was needed, he continued. Today, however, in people who may be taking the newer, direct-binding, non-vitamin K DOACs (also called NOACs), determining coagulation status is far less simple. “The problem, in the acute setting, is that you may not know if the patient is on any of these newer drugs and very often, when patients do come in, they themselves may or may not know what they are taking, and family members may not know either,” Goldstein said.

Now, in a new study, Matthias Ebner, MD (Charité University Medicine, Virchow Klinikum, Berlin, Germany), and colleagues make the case that while reagent-specific assays and cutoffs may not be needed for routine monitoring, they could play an important role in emergency management.

“This study demonstrates that results of global coagulation tests within normal range are not suited to safely identifying DOAC concentrations below the suggested safe-for-treatment threshold of 30 ng/mL,” the authors conclude. Their paper appeared online August 3, 2017, in Stroke.

Different Tests, Different Answers

Ebner and colleagues reviewed 481 blood tests from 96 DOAC-treated patients seen at two different hospitals. Patients were taking apixaban, dabigatran, or rivaroxaban, and blood samples were taking over the course of 12 to 24 hours and tested using a range of assays: prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) as well as DOAC-specific assays (anti-Xa activity, diluted TT). Finally, liquid chromatography–tandem mass spectrometry was used as the gold standard against which the other tests were compared.

According to the study authors, PT and aPTT tests within the normal range provided relatively low specificity for identifying DOAC concentrations for all three drugs and combining the two tests did not improve their accuracy. For the 34 patients taking dabigatran, a normal TT demonstrated 100% specificity for dabigatran levels but low sensitivity, at 26%.

By contrast, using DOAC-specific cutoffs delivered better results, attaining greater than 95% specificity for rivaroxaban and dabigatran, although no such cutoff could be established for apixaban.

Results of PT and aPTT assays within the normal range are often considered to be sufficient when testing concentrations of dabigatran and rivaroxaban, particularly if sensitive reagents are used. The current study, however, suggests that a substantial proportion of patients would be identified as being eligible for additional anticoagulation, despite having drug concentrations much higher than those detected by the available assays.

“Test results within the normal range should therefore not be used to guide emergency treatment decisions,” they say. Less data is available for apixaban, but given the lack of specificity seen in their analysis, the authors believe use of “normal” results for PT and aPTT in apixaban-treated patients is also not supported.

Even using TT tests in the normal range for dabigatran is problematic, they note, since tests would correctly identify patients with therapeutic amounts of anticoagulation on-board, but would miss more than two-thirds of patients who are not appropriately anticoagulated.

At this time, Ebner et al conclude, “the use of test results within normal range should become obsolete for the identification of patients suitable for thrombolysis in acute ischemic stroke or emergency surgery.”

A New Era

In an email to TCTMD, Sven Poli, senior author on the study, estimated that roughly one in five hospitals are not equipped with DOAC-specific tests and even if they have them, turnaround times can be long.

By contrast, he continued, “these ‘global/unspecific’ coagulation tests are available in all hospitals; this is why we suggest our approach of using these tests," but with DOAC specific cutoffs.

Goldstein, who was not involved in the current study, told TCTMD that Ebner et al’s paper essentially confirms what many physicians are already worried about, namely that the gold standard tests of old cannot be relied upon in the current era.

“The currently guidelines say that if a patient is receiving a DOAC, they shouldn’t be treated unless you have a specific assay” he said. “The problem is, those tests aren’t necessarily universally available and we are often operating in individual patients not knowing if they are therapeutically anticoagulated or not.”

The solution depends on individual circumstances, Goldstein said. If you know a patient is taking a specific agent, then the specific assay can be ordered. If not, there needs to be a “battery of tests” in order to detect levels of both dabigatran and the anti-Xa inhibitors. Asked about apixaban, which appeared to be an outlier in the current study, Goldstein noted that a specific test for apixaban is now available. Indeed, most drugs can be detected using point-of-care tests, he added, although some hospitals may rely on centralized laboratories. In most cases, centers will typically begin stroke treatment in an urgent stroke patient and will then stop treatment if a test comes back positive.

Asked whether he and his co-authors had any data to suggest that inaccurate coagulation tests were leading to worse outcomes, Poli said: "Data to prove this assumption does not exist, but, for example, thrombolysis in acute ischemic stroke might not be performed in a significant fraction of patients despite safe DOAC plasma concentrations."

 ​​​​All the same, there are important takeaways from the current study, Goldstein concluded. “It reinforces the fact that the PT/aPTT can’t be used as a screen for therapeutic anticoagulation and that hospitals who are caring for patients with acute stroke . . . need to consider making and having these tests available and used as part of their routine practice.”