Reversal of the Antithrombotic Action of New Oral Anticoagulants

Study Overview
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Brief Summary
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The main goal of this study is to improve safety and efficiency of clinical practice with the new generation of oral anticoagulants. To determine the effect of new oral anticoagulants (dabigatran and rivaroxaban) on platelets and coagulation mechanisms under flow conditions. To evaluate the ability of the concentrates containing coagulation factors (PCCs and FVIIa) to reverse the effects induced by the new anticoagulants. These studies will be carried out ex vivo in blood samples obtained from healthy volunteers undergoing oral anticoagulant therapy at doses of proven efficacy and safety used in previous clinical trials.

Detailed Description
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There is a lack of information on antidotes that could reverse the effects of new oral anticoagulants in patients that require a rapid restoration of their impaired hemostatic mechanisms. The present study seeks to improve the security and efficacy of the clinical practice with the new generation of oral anticoagulants. OBJECTIVES: To assess the action of new oral anticoagulants (dabigatran y rivaroxaban) on hemostasis with specific interest on possible interference with platelet interactions and coagulation mechanisms under flow conditions; To evaluate comparatively the effects of coagulation factor concentrates of established efficacy (prothrombin complexes and rFVIIa) to reverse the alterations of hemostasis parameters induced by the new anticoagulants. METHODOLOGY: Studies will be performed ex vivo using blood samples from healthy individuals subjected to treatments with the new anticoagulants at doses of proven efficacy and safety (150mg/12 h for dabigatran and 20 mg/day for rivaroxaban). Blood samples from the participants will be spiked in vitro with know concentrations of the coagulation factors. Modifications in: morphometric parameters (platelet deposition and fibrin formation) in perfusion studies under flow conditions; and analytical tests evaluating changes in coagulation mechanisms (thrombin generation, ecarine and prothrombin times) will be determined.

Official Title
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Evaluation of the Potential Action of Coagulation Factors Concentrates in the Reversal of the Antithrombotic Action of New Oral Anticoagulants: Studies ex Vivo in Blood Samples From Healthy Volunteers

Conditions
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Thrombosis, Anticoagulant-induced Bleeding, Anticoagulant Overdosage, Hemorrhage

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Dabigatran


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers ages from 21 to 60 years Approval informed consent Exclusion Criteria: History of hepatic or kidney disease Previous history of hemorrhagic or thrombotic disease Pregnancy or breast feeding Concomitant use of drugs affecting hemostasis Use of medications of herbal treatments that could interfere with the pharmacokinetics or pharmacodynamics of the study drug (according to manufacturers label) Practice of risky sports (during the study period) Blood donation in the previous 3 months

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rivaroxaban<br>Healthy donors subjected to 20mg/day for 5 days | Drug: Rivaroxaban<br>* 20 mg/day, oral administration maintained for 5 days<br>* Other names: Xarelto is the brand name for rivaroxaban;|
| Active Comparator: Dabigatran<br>Healthy volunteers subjected to 150 mg/12hours for 5 days | Drug: Dabigatran<br>* 150 mg/12 hours, administered orally, treatment maintained for 5 days<br>* Other names: Pradaxa is the brand name for dabigatran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modifications in hemostasis parameters. | We will evaluate: a) the surface covered by platelets and fibrin on the subendothelium of vascular segments. Platelet interaction will be expressed as percentage of covered surface by platelets (%CS) and classified as contact, adhesion and aggregates depending of the size of interactions. Fibrin formation will be also evaluated as percentage of surface covered by fibrin (%F) and as the mean area of fibrin formed; and b) thrombin generation as lag time and maximum thrombin peak generation using a commercially available test (Technothrombin TGA, Technoclone GMBH). | 5 days | 
| Changes observed after in vitro addition of coagulation factor concentrates | We will re-evaluate: a) the surface covered by platelets and fibrin on the subendothelium of vascular segments. Platelet interaction will be expressed as percentage of covered surface by platelets (%CS) and classified as contact, adhesion and aggregates depending of the size of interactions. Fibrin formation will be also evaluated as percentage of surface covered by fibrin (%F) and as the mean area of fibrin formed; and b) thrombin generation as lag time and maximum thrombin peak generation using a commercially available test (Technothrombin TGA, Technoclone GMBH). | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure other indirect biomarkers of the activation of the coagulation mechanisms. | Prothrombin time, ecarin clotting time, and F1+2 fragments will be determined in frozen plasma samples. | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dabigatran, rivaroxaban, oral anticoagulants, coagulation, bleeding, plasma concentrates