TRAPS (Trial on Rivaroxaban in High Risk Patients with

TRAPS (Trial on Rivaroxaban in High Risk
Patients with AntiPhospholipid Syndrome,
(ClinicalTrials.gov Identifier: NCT02157272)
Background (1)
• Triple positivity (LAC+, aCL+, aβ2GPI+, same isotype) in
APS is associated with thromboembolic events and
severe pregnancy morbidity
• Triple positive APS patients are at high risk of recurrent
thromboembolic events.
Cumulative incidence of thromboembolic
events in high risk triple positive APS
patients (n=160)
Pengo V, JTH 2010
Background (2)
• As compared with aspirin, AVK therapy significantly
reduces thromboembolic recurrences, although it might
prove insufficient in some cases.
High risk triple positive APS patients (n=160)
Pengo V, JTH 2010
Background (3)
• The new oral anticoagulant rivaroxaban, an inhibitor of factor
Xa, is at least as effective and safe as warfarin in preventing
venous and arterial thromboembolism and significantly
reduces cerebral bleeding.
• Rivaroxaban does not need laboratory control thus being very
much appreciated by the young population of patients with
APS. At variance with other new anticoagulants it is
administered once daily favoring patients compliance.
A prospective, randomized clinical Trial comparing
Rivaroxaban vs warfarin in high risk patients with
AntiPhospholipid Syndrome (TRAPS)
European clinical trials database 2013-004575-13
Study Design:
Phase III, Randomized, open label, non inferiority, prospective,
multicenter, non-profit.
Primary Objective:
To determine the efficacy and safety of rivaroxaban as compared to
warfarin in the thrombosis prevention of triple aPL-positive APS
patients.
Inclusion criteria
• Age 18-75
• Persistent (at least 12 weeks apart) triple
aPL-positivity
• History of thrombosis (arterial, venous,
and/or biopsy proven microthrombosis)
according to Miyakis.
Exclusion criteria (I)
•
Creatinine clearance <30 mL/min at the
screening visit (calculated by mean of
Cockroft-Gault formula)
•
Current or programmed pregnancy.
•
Patients taking interfering medications:
proteases inhibitors (HIV infection) or
systemic antifungal therapy with oral
azole drugs.
Confirmation of triple positivity
• To confirm triple positivity for aPL and to
validate the laboratory diagnosis, plasma
from patients of each Center will be
stored and later on retested in a
reference laboratory (Padua Thrombosis
Centre).
Randomization
• Rivaroxaban 20mg/qd or rivaroxaban 15mg/qd if creatinine
clearance 30-50ml/min.
• Warfarin to maintain an INR between 2.0 and 3.0
In patients not on warfarin at the time of randomization low
molecular weight heparin until INR value is ≥2.0 will be used.
In patients on warfarin at the time of randomization and
randomized to rivaroxaban, rivaroxaban is started when INR is
below 1.5.
Outcome measure
•The primary end point is cumulative of incident thrombosis
(arterial or venous), major bleeding (ISTH) and death
•Thrombosis must be confirmed by appropriate imaging studies.
Statistical Calculations & Analysis
•A non-inferiority logrank test with an overall sample size of 535
subjects (267 in the reference group and 268 in the treatment
group) achieves a power 80.0% at a 0.05 significance level
•The study lasts for 4 years of which subject accrual (entry)
occurs in the first 2 years.
•An interim analysis will be carried out after two years from the
date in which the first patient was randomized.
TRAPS trial
Study starts: 2015
Study ends: 2019
[email protected]
TRAPS eCRF
Centri con approvazione del rispettivo Comitato Etico
PD01= Padova Cardiologia
PD02=Padova Reumatologia
BS01=Brescia Reumatologia
VI01=Vicenza Ematologia
PG01=Perugia Medicina Interna
RE01=Reggio Emilia Medicina Interna
CA01=Cagliari Medicina Interna
CR01=Cremona Centro Trombosi
MI01=Milano Gaetano Pini
MI02=Milano Policlinico
MI03=Milano S.Paolo
BE01=Bergamo Trasfusionale
RO1=Roma Ematologia
LE01=Lecco Immunotrasfusionale
FI01=Firenze Medicina Interna
TRAPS
Brescia
Padova 1
Padova 2
Number of randomized patients
15
Perugia
Vicenza
10
Cremona
Reggio Emilia
Cagliari
5
Milano 2
Milano3
0
Centers
Centri in attesa di approvazione del Comitato Etico locale
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Pisa1=Patologia Clinica
Pisa2=Immunoallergologia
Torino=Immunomatologia
Roma2=Medicina interna
Roma3:Reumatologia
Alessandria=Emostasi e Trombosi
Bologna=angiologia
Napoli=medicina Interna
Bari/Monopoli=Centro trasfusionale
Foggia=Emostasi e Trombosi
Catanzaro=Emostasi e Trombosi
Palermo=Medicina Interna
Siena=Medicina Interna
Centri Europei
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Parigi 1
Parigi 2
Cracovia
Vienna
Saragozza
Madrid
Barcellona
Ginevra
Atene
Organigramma dello studio
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Coordinatore: Vittorio Pengo (Padova)
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Steering Committee: Vittorio Pengo (Padova), Amelia Ruffatti (Padova),
Angela Tincani (Brescia), Pierluigi Meroni (Milano)
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Comitato di aggiudicazione degli eventi: Gualtiero Palareti (Bologna), Paolo
Prandoni (Padova)
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Comitato che si occuperà della stesura del manoscritto: Vittorio Pengo
(Padova), Alberto Tosetto (Vicenza), Amelia Ruffatti (Padova).
Nomi degli autori nel manoscritto (Authorship)
• 1-5 pazienti randomizzati: 1 co-autore
• 6-10 pazienti randomizzati: 1 co-autore più uno in Appendice
(Appendix) indicizzata.
• >10 pazienti randomizzati: 2 co-autori più uno in Appendice
(Appendix) indicizzata.
Emendamenti e suggerimenti
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E’ stato approvato un emendamento che estenderà l’età per l’arruolamento
dei pazienti fino a 75 anni. (verra inviata notifica a tutti i CE)
E’ NECESSARIO compilare TUTTI i campi indicati nel format di ciascun
paziente in RedCap;
E’ SUFFICIENTE avere almeno un pregresso test che dimostri la triplice
positività del paziente;
Se il paziente è in Sintrom ed è randomizzato a Warfarin si ricorda che la
dose giornaliera di warfarin in mg è approssimativamente doppia di quella
del Sintrom.
Gli eventi avversi seri e quelli che compongono l’end point primario
(tromboembolismo, emorragia maggiore e morte) vanno trasmessi al Centro
coordinatore con la documentazione necessaria alla aggiudicazione
dell’evento.
Lettera ai Centri del 23 settembre
• In accordo con i componenti dello steering committee, si
suggerisce che i pazienti che entrano nello studio
TRAPS ed hanno patologia tromboembolica arteriosa
(stroke/tia, ima etc) debbano essere trattati sia con
l’anticoagulante (warfarin o rivaroxaban) che con
aspirina 100mg/die. Infatti non è chiaro se questi siano
eventi cardio-embolici o aterotrombotici o da vasculite
CARDIOGENIC CEREBRAL ISCHEMIA IN PATIENTS
WITH ANTIPHOSPHOLIPID SYNDROME: SOURCE
OF THROMBI EUROPEAN PROJECT (STEP)
Type and rate of alterations at TEE
A=valvular thickening
B=Valvular incompetence
C=Mitral prolapse
D=Patent foramen ovalis
E=vegetations
F=echocontrast
G=patients with alterations
100
90
80
70
60
50
40
30
20
10
0
A
B
C
D
E
F
G
Valvular Thickening
Aortic arch plaque