CLN Article

Testing Dilemmas for Direct Oral Anticoagulants

While Waiting for FDA-Approved Assays, Labs Contend With Current Tests’ Flaws

Deborah Levenson

Direct oral anticoagulant (DOAC) drugs—Xarelto (rivaroxaban), Eliquis (apixaban) Pradaxa (dabigatran etexilate), and Savaysa (edoxaban)—are alternatives to warfarin for prevention of blood clots and stroke in patients at risk of deep venous thrombosis, pulmonary embolism, and post-surgical clots. DOACs are much more expensive than warfarin, but have distinct advantages, including a comparatively wide therapeutic window, fewer interactions with other drugs, and relatively short half lives that make them easier to stop abruptly. In addition, except for dabigatran, DOACs have multiple clearance mechanisms. Most appealing to patients, DOACs don’t need routine monitoring.

Until recently, no Food and Drug Administration (FDA)-approved antidote to DOACs was available, tempering many clinicians’ enthusiasm for these agents. But with the October 2015 FDA approval of Praxbind (idarucizumab), an antidote for dabigatran, and with other reversal agents in development, the drugs are poised to become more popular.

Meanwhile, clinicians and laboratorians struggle both with the lack of antidotes to the other three drugs as well as a dearth of FDA-approved assays that measure DOACs’ activity. “Any time you’re going to do procedures, it’s always important to know what to expect in terms of the risk of bleeding and so . . . having a precise measure of patients’ level of anticoagulation is going to be important,” Frederick Korley, MD, PhD, told FDA officials at an October 2015 workshop on the future of DOAC-specific testing.

Korley, an assistant professor of emergency medicine at Johns Hopkins University School of Medicine in Baltimore, and other clinicians pointed to a variety of situations in which patients may benefit from such testing. These include emergency surgery, breakthrough bleeding and thrombosis, noncompliance, and drug interactions, particularly in patients with atrial fibrillation and acute ischemic stroke, and those who are obese, underweight, elderly, or who have renal insufficiency.

In the absence of FDA-approved assays specifically designed to measure DOAC concentrations, other lab-developed tests (LDTs) provide some of the information clinicians need, but little research data informs the relationship between DOAC levels and clinical outcomes.

PT and APTT: Missing the Mark

Routine, widely available coagulation screening assays—including prothrombin time (PT) and activated partial thromboplastin time (APTT)—don’t reliably measure various DOACs’ anticoagulant effects. The sensitivity of these tests varies with different reagents and drugs, and can’t be standardized across laboratories, according to Adam Cuker, MD, assistant professor of medicine, pathology, and laboratory medicine at the University of Pennsylvania Perelman School of Medicine, who wrote a review article on the subject (J Am Coll Cardiol 2014;64:1128–39). In addition, DOACs and warfarin inhibit different parts of the coagulation cascade. Warfarin inhibits coagulation factors II, VII, IX, and X, but dabigatran inhibits thrombin, and rivaroxaban, apixaban, and edoxaban inhibit activated factor X (Xa), Cuker said in an interview. Meanwhile, PT and APTT’s linearity, sensitivity, and reproducibility don’t sufficiently enable quantification across a broad range of drug levels.

The good news is DOAC concentration can be measured with other methods. Mass spectrometry is the gold standard, but most clinical laboratories don't offer it because of the test's complexity and their lack of necessary instruments. Quicker options include dilute thrombin time, ecarin methods, and chromogenic anti-Xa, which all require calibrators and controls specific for particular DOACs. However, only a few centers offer these tests, usually just during business hours, according to Cuker.

On the Horizon

Some companies are now marketing DOAC-specific assays in Europe and hoping to get FDA approval for the tests, they said during the FDA workshop. Bedford, Massachusetts-based Instrumentation Laboratory markets reagent test kits, calibrators, and tests for dabigatran and rivaroxaban validated on its own instruments, while Parsippany, New Jersey-based Stago Diagnostics sells quantitative DOAC assays differentiated from each other by calibrators and controls developed for each of the drugs.

Perosphere in Danbury, Connecticut, is working on multiple products, including an assay sensitive to all of the approved DOACs, and an accompanying point-of-care device that measures various anticoagulants and reversal agents. A reversal agent for Xa and IIa inhibitors is also in development.

At the workshop, FDA officials noted the need for a regulatory pathway that would speed approval of new DOAC tests, but as of May 2016, the agency had taken no definitive steps toward that goal. Part of the problem is that the type and extent of information needed for reviewing new tests depends on the tests’ intended uses, and clinicians are conflicted about what the uses should be, said FDA press officer Lyndsay Meyer. While some clinicians have told FDA they want tests to give “quantitative measurement of DOAC presence or activity, particularly in emergency situations,” others have also “expressed concern regarding the interpretability of test results in the absence of a well-defined therapeutic range for drug levels or activity.” Without a therapeutic range, it is difficult for FDA to see that tests are safe and effective, Meyer added.

Companies are unlikely to pay for the large studies needed to produce the data to establish a therapeutic range, noted Cuker. He questioned the logic of requiring one, noting that FDA seems to be treating DOAC tests like warfarin. Unlike warfarin, DOACs do not require routine monitoring and tests to measure their concentration are used only in special, relatively circumscribed situations. DOAC-specific testing is more like toxicology tests for high or low levels of a drug, he added.

Cuker suggested that instead of requiring therapeutic ranges correlated to patient outcomes, FDA should consider requiring only “on-therapy” ranges—trough and peak levels associated with good patient outcomes. “That’s the best we can do right now,” he observed.

Measuring DOACs in Practice

The University of California, Davis (UC Davis) Health System’s special coagulation section of pathology and laboratory medicine in Sacramento is one of the few U.S. hospital labs to provide regular DOAC testing. The lab implemented ecarin testing for dabigatran in 2011, and anti-Xa testing calibrated for rivaroxaban and apixaban in 2013 and 2015, respectively. Because this type of testing isn’t routine and the lab has staffing limitations, these tests are available only during set weekday hours, noted Robert Gosselin, CLS, a senior specialist in the lab.

To help clinicians, UC Davis DOAC test reports list factors that can affect dabigatran concentration, such as renal function, dosage, administration frequency, and if the drug has been taken with food. Reports note no established therapeutic range for apixaban and a predicted trough concentration of the drug in non-valvular atrial fibrillation patients. UC Davis reports also recommend measuring trough levels in patients taking 20 mg of rivaroxaban once daily for continued deep venous thrombosis treatment.

Gosselin suggested that labs looking at routine DOAC testing consider using blood samples collected at peak or trough levels and at timed intervals to compare reported results to published findings.

Cuker, who is considering offering DOAC-specific tests around-the-clock in his automated lab, noted challenges to doing so. These include ensuring appropriate quality assurance and quality control, and adequately training technicians who work on three different shifts and “may go a year without doing a test and then need to do one in the middle of the night.”

Another challenge to and possible disincentive for DOAC testing implementation is FDA’s plan to impose new regulatory requirements for all LDTs, Gosselin added.

Despite these difficulties, providing DOAC testing is the right thing to do, Gosselin maintained. “It’s awful to be in a situation where you can’t provide clinicians with the information and tools they need to move forward with patient management, especially in the acutely ill or bleeding patient,” he said.

Deborah Levenson is a freelance writer based in College Park, Maryland. Email: [email protected]