Study Design for Evaluating an In Vitrodiagnostic Test for Direct Oral Anticoagulants

Determining the anticoagulant effect of direct oral anticoagulants (DOACs) can be important for rapid medical decision-making, especially in patients needing immediate management. Chromogenic and coagulation methods have several limitations, including limited accuracy, long turnaround time, and the need for specialized laboratories to carry out the tests. The in vitrodiagnostic (IVD) DOAC Dipstick test screens for the absence or presence of a DOAC and can help accelerate treatment decisions in these situations.

DOAC Dipstick is a CE-marked IVD that qualitatively determines direct oral factor Xa and thrombin inhibitors by visual analysis of colour following a chemical reaction of a urine sample with specific pads on a test strip. A prospective, open-label, controlled, non-randomized, post-marketing study is currently underway and the primary endpoint is to ensure that the true positive and the true negative rate of the IVD results are above 95% compared with liquid chromatography tandem mass spectrometry (LC-MSMS) results. Secondary endpoints are: a) Comparison of IVD results with those of a reflectance photometric reader (DOASENSE Reader), b) determining the sensitivity and specificity of the DOASENSE Reader results using DOAC concentrations determined by LC-MS/MS, and c) to investigate IVD handling and user satisfaction using a questionnaire. Two groups of patients are being included into the study: a) Patients being treated with oral direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) (n = 440), and b) patients being treated with an oral thrombin inhibitor (dabigatran) (n = 440). Inclusion criteria are ≥18 yearsof age and rivaroxaban, apixaban, and edoxaban or dabigatran treatment for at least 1 week. The sample size calculation was based on a proportion of false negative and false positive IVD tests below 5%. The sample size of n = 384 per group was assessed to demonstrate that the assumed rate of 2.5% false negative/false positive results is significantly lower than 5% (α=0.05 and β=0.20).Assuming a dropout rate of 12% yielded a sample size of n = 440 patients per group. This sample size was assessed with the SAS procedure PROC POWER (SAS Institute Inc., Cary, NC, USA, release 9.4) using the ONESAMPLEFREQ statement.

The study started at the end of August 2018. To allow study termination within 6 months, 20 centres in Germany were selected and all agreed to participate. The current inclusion rate is somewhat higher than calculated. So far, no results have indicated that the study should be terminated earlier.

If the primary endpoint of the study is achieved, the IVD DOAC Dipstick may offer a diagnostic tool to rapidly and specifically determine the absence or presence of both direct oral factor Xa and thrombin inhibitors within minutes in one coagulation test.