A Randomized Clinical Trial of Resuming Direct Oral Anticoagulant Therapy Following Major Hemorrhage

2020-01-22 12:12:57 | BioPortfolio


Primary Objective:

To determine the optimal time to initiate anticoagulation with Direct Oral Anticoagulants (DOACs) following major hemorrhage in patients with non-valvular atrial fibrillation or VTE.

Primary Outcome: 60-day composite of thromboembolic events, defined as DVT, pulmonary emboli, myocardial infarctions, ischemic strokes and systemic emboli, and bleeding events defined as non-CNS major bleeding events (modified BARC3 or above 7) worsening index tICrH or new intracranial hemorrhage (ICrH).

Secondary Objectives:

To compare 60 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups To compare 60 day clinical outcomes by the Glasgow Outcome Scale-Extended (GOS-E) among the time-to-treatment groups To explore the optimal timing in subgroups of age, sex, outcome category, and NOAC choice


The trial will employ an innovative adaptive design using time as a dose (1, 2 and 4 weeks) and adapting randomization probabilities to the better performing doses. Entry into the trial is driven pragmatically by clinician intent to restart a DOAC after any anticoagulant-associated tICrH and willingness randomize to the specified time intervals. We include as indication for anticoagulation atrial fibrillation and VTE. We exclude mechanical valves and ventricular assist devices (VADs) and the coronary and/or peripheral artery disease low-dose DOAC indication. As all groups are anticoagulated, we do not expect separation of event curves beyond 60 days. This is a secondary prevention trial, not a TBI treatment trial, and is thus powered on these events. However, we will also collect 90-day Glasgow Outcome Scale-Extended (GOS-E)and modified Rankin Scale (mRS) to explore weighting of the components of the composite, and we will perform a secondary analysis removing DVT, the lowest mortality event, from the thrombotic component. We will employ early stopping for futility or superiority of one arm (defined under statistical analysis plan). The sample size is 1,100 patients (expected 10% lost to follow up leaving 1,000 analyzable) which gives us 0.86 power at an alpha of 0.05 (based on expected thrombotic event rates of 3, 6 and 9% and bleeding rates of 1, 0.67 and 0.33% at 1, 2 and 4 weeks)). Restarting is limited to DOACs (though anticoagulant at index tICrH is not) as opposed to vitamin K antagonists (VKA). VKA delayed onset would confound a timing trial, and heparin bridging is not standard in atrial fibrillation, which we expect to be the majority indication. DOACs represented greater than half of 2018 trial network anticoagulated tICrH and are rapidly rising. The US Food and Drug Administration (FDA) approved aDOAC generic (apixaban) in 2019, likely accelerating uptake. DOACs are associated with lower overall ICrH risk. Excluding VKA acts as a check on mechanical valve or VAD enrollment, for which our time intervals may not be appropriate.

Study Design






Not yet recruiting


University of Texas at Austin

Results (where available)

View Results


Published on BioPortfolio: 2020-01-22T12:12:57-0500

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Medical and Biotech [MESH] Definitions

Agents that affect the function of FIBRIN in BLOOD COAGULATION. They used as COAGULANTS for HEMORRHAGE or ANTICOAGULANTS for THROMBOSIS.

Hemorrhage within the orbital cavity, posterior to the eyeball.

Intraocular hemorrhage from the vessels of various tissues of the eye.

Hemorrhage following any surgical procedure. It may be immediate or delayed and is not restricted to the surgical wound.

The sudden loss of blood supply to the PITUITARY GLAND, leading to tissue NECROSIS and loss of function (PANHYPOPITUITARISM). The most common cause is hemorrhage or INFARCTION of a PITUITARY ADENOMA. It can also result from acute hemorrhage into SELLA TURCICA due to HEAD TRAUMA; INTRACRANIAL HYPERTENSION; or other acute effects of central nervous system hemorrhage. Clinical signs include severe HEADACHE; HYPOTENSION; bilateral visual disturbances; UNCONSCIOUSNESS; and COMA.

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