Reversal of the Antithrombotic Action of New Oral Anticoagulants (REVANT)

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

The main goal of this study is to improve safety and efficiency of clinical practice with the new generation of oral anticoagulants.

1. To determine the effect of new oral anticoagulants (dabigatran and rivaroxaban) on platelets and coagulation mechanisms under flow conditions.
2. 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.

Study Overview

• Status: Unknown
• Conditions: Hemorrhage; Thrombosis; Anticoagulant-induced Bleeding; Anticoagulant Overdosage
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Dabigatran

Detailed Description

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:

1. 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;
2. 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.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic, Fundació Clinic (FCRB)
    • Contact: Gines Escolar; Phone Number: 34932275448; Email: gescolar@clinic.ub.es
    • Sub-Investigator: Eduardo Arellano, M.D., Ph.D.
    • Sub-Investigator: Xavier Carne, M.D., Ph.D.
    • Principal Investigator: Gines Escolar, M.D., Ph.D.
    • Sub-Investigator: Ana M Galan, Ph.D.
    • Sub-Investigator: Juan Carlos Reverter, M.D., Ph.D.
    • Sub-Investigator: Jaume Villalta, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gines Escolar
• Collaborators: Ministry of Health, Spain
• Investigators: Principal Investigator: Gines Escolar, M.D., Ph.D., Fundacio Clinic per a la Reçerca Biomedica (FCRB)

Publications and helpful links

General Publications

• Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, Molina P, Reverter JC, Carne X, Villalta J, Tassies D, Lozano M, Diaz-Ricart M, Escolar G. Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers. Transfus Med Rev. 2015 Oct;29(4):242-9. doi: 10.1016/j.tmrv.2015.08.001. Epub 2015 Aug 8.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Anticipated): December 1, 2012
• Study Completion (Anticipated): December 1, 2012

Study Registration Dates

• First Submitted: November 8, 2011
• First Submitted That Met QC Criteria: November 21, 2011
• First Posted (Estimate): November 23, 2011

Study Record Updates

• Last Update Posted (Estimate): March 12, 2012
• Last Update Submitted That Met QC Criteria: March 9, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: bleeding; oral anticoagulants; coagulation; rivaroxaban; dabigatran; plasma concentrates
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Hemorrhage; Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran
• Other Study ID Numbers: FCRB; 2010-022985-29 (EudraCT Number)