nao - asl novara · nao complicanze emorragiche gestione condivisa della terapia anticoagulante e...
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Dr. Roberto Frediani
Medicina Interna ASL TO5
Dipartimento Formazione FADOI
NAO complicanze emorragiche
Gestione condivisa della terapia
anticoagulante e antiaggregante
Relazioni con soggetti portatori di interessi commerciali in campo
sanitario
Il sottoscritto Dr. Roberto Frediani ai sensi dell’art. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dell’Accordo Stato-Regione del 5 novembre 2009, dichiara che negli ultimi due anni NON ha avuto rapporti diretti di finanziamento con soggetti portatori di interessi commerciali in campo sanitario.
emorragie e VKA “major bleeding” definizione mortalità ed emorragie buon profilo per emorragie cerebrali, ma …. sanguinamenti gastroenterici
AGENDA studi clinici e mondo reale
che fare ?
il documento
Cause comuni di aumentato rischio emorragico con la terapia anticoagulante
• Cause endogene – insufficienza renale – insufficienza epatica – altri fattori di rischio: età - recenti sanguinamenti (GI,
intracranici, …) - ipertensione grave non controllata - retinopatia vascolare - ulcere GI attive - malformazioni vascolari intraspinali/intracerebrali - recente neurochirurgia od oftalmica
• Cause esogene – Sovradosaggio accidentale o volontario del farmaco – Associazione con antiaggreganti: ASA, clopidogrel, FANS, … – Associazione con altri farmaci che interferiscono con
assorbimento o metabolismo
Major and Fatal Bleeding are High with VKA in
NVAF Patients in Real Life
Study drug Patients
(n)
Rate of major bleeding
(%/year)
Fatal bleeding
(%)
Warfarin starters1 125,195 3.8 1.6
VKA starters2 820 6.5 2.3
VKA starters3 682 6.0 1.0
Warfarin users4 261 5.3* 0.4
Coumarin derivative
users5 10,757 7.2 0.3
Major bleeding:
~6–8%/year
#Values are calculated (not reported); *In the first year.
1. Gomes T et al. CMAJ. 2013;185(2):E121–127; 2. Beyth RJ et al. Am J Med. 1998;105(2):91–99;
3. Steffensen FH et al. J Intern Med. 1997;242(6):497–503; 4. Gitter MJ et al. Mayo Clin Proc. 1995;70(8):725–733;
5. Linkins LA et al. Ann Intern Med. 2003;139(11):893–900;
Fatal bleeding:
~1.5%#
Definition of Major Bleedings
in the large Phase III NOACs Trials
RE-LY ROCKET AF ARISTOTLE ENGAGE AF
Major Bleeding: ≥ 1
of:
1. With Hb ≥ 2.0 g/dl
2. With transfusion ≥ 2 U
blood or packed cells
3. Symptomatic ocular,
cranial, spinal, intra-
muscular with
compartment
syndome,
retroperitoneal,
pericardial
Major Bleeding : ≥ 1
of:
1. With Hb ≥ 2.0 g/dl
2. With transfusion ≥ 2 U
blood or packed cells
3. Symptomatic ocular,
cranial, spinal, intra-
muscular with
compartment
syndome,
retroperitoneal,
pericardial
Major Bleeding : ≥ 1
of:
1. With Hb ≥ 2.0 g/dl
2. With transfusion ≥ 2 U
blood or packed cells
3. Symptomatic ocular,
cranial, spinal, intra-
muscular with
compartment
syndome,
retroperitoneal,
pericardial
Major Bleeding : ≥ 1
of:
1. With Hb ≥ 2.0 g/dl
2. With transfusion ≥ 2 U
blood or packed cells
3. Symptomatic ocular,
cranial, spinal, intra-
muscular with
compartment
syndome,
retroperitoneal,
pericardial
1.Fatal bleeding, and/or
2.Symptomatic bleeding in a critical area or
organ, (intracranial, intraspinal, intraocular, retroperitoneal,
intraarticular or pericardial, or intramuscular with
compartment syndrome), and/or
3.Bleeding causing a fall in hemoglobin level of ≥
2.0 g/dL, or leading to transfusion of two or
more units of whole blood or red cells. Schulman S et al. J Thromb Haemost 2005
Principali sedi di sanguinamento maggiore HR rispetto a Warfarin
Sede Dabigatran
110 mg
150 mg
Rivaroxaban Apixaban Edoxaban
60 mg
30 mg
Gastrointestinali 1.10
1.50
1.45 0.89 1.23
0.67
In organo o area
critica
? 0.69 ? 0.51
0.32
Hb ≥ 2 dr/dL ? 1.22 ? 0.98
0.56
Pericolosi per la
vita
0.81
0.68
<< ? 0.51
0.32
Clinicamente
rilevanti (non
maggiori)
?
<< 0.68* 0.86
0.66
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011; Giugliano RP et al NEJM 2013
* Maggiori e non maggiori cllinicamente rilevanti
Conclusion:
The MB incidence rate among rivaroxaban users with NVAF is low in a post-market setting, and generally similar to the registration trial.
Tamayo et al., Clin Cardiol 2015
To provide longitudinal safety data by obtaining information associated with MB
among rivaroxaban users with NVAF
Objective Major Bleed Characteristics*
*MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites.
Characterizing MB in patients with NVAF: a pharmacovigilance study of 27.467 patients taking rivaroxaban
• Observational cohort study • US Department of Defense electronic
health care records • Rates of major bleeding, any bleeding,
ICH, fatal bleeding, GI bleeding • Endpoint definition approved by FDA
Design
Rivaroxaban was associated vs warfarin with a
Significant 47% reduction in ICH
Non-significant 29% decrease in ischemic stroke
Significant 39% reduction in the combined endpoint of ICH and ischemic stroke
REVISIT US - Significant Reduction in the Combined Endpoint for Rivaroxaban vs warfarin
Rivaroxaban Warfarin HR (95% CI)
rivaroxaban vs.
warfarin
HR (95% CI)
rivaroxaban vs. warfarin Rate
(%/year)
Rate
(%/year)
ICH 0.49 0.96 0.53 (0.35–0.79)*
Ischemic stroke 0.54 0.83 0.71 (0.47–1.07)
Combined 0.95 1.6 0.61 (0.45–0.82)*
Favors rivaroxaban
Favors warfarin
*p<0.05
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States
(REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx
Gastrointestinal
Bleeding
Intracranial
Bleeding
1.25 (1.01 - 1.55)
0.48 (0.39 - 0.59)
Risk Ratio (95% CI)
p=0.043
p<0.0001
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Heterogeneity Intracranial Haemorrhage, p = 0.22
Gastrointestinal Bleeding, p = 0.009
Intracranial and Gastrointestinal Bleedings ‘High dose’ regimens for dabigatran and edoxaban
Dabigatran 150 mg, Edoxaban 60 mg, Rivaroxaban, Apixaban
Ruff CT, et al. Lancet 2013. Dec 3. Epub ahead of print]
Gastrointestinal
Bleeding
Intracranial
Bleeding
0.89 (0.57 - 1.37)
0.31 (0.24 - 0.41)
Risk Ratio (95% CI)
p=0.58
p<0.0001
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Heterogeneity Intracranial Haemorrhage, p = 0.90
Gastrointestinal Bleeding, p = 0.01
Intracranial and Gastrointestinal Bleedings ‘Low dose’ regimens for dabigatran and edoxaban
Dabigatran 110 mg, Edoxaban 30 mg, Rivaroxaban, Apixaban
Ruff CT, et al. Lancet 2013. Dec 3. Epub ahead of print]
NOACs: indicazioni da RCP
Preparato Indicazioni
Dabigatran Interruzione del farmaco
Favorire la diuresi; dialisi
FEIBA, fVIIa o PCC 3 fattori
Consultare esperto in coagulazione
Rivaroxaban Interruzione del farmaco
PCC o FEIBA, fVIIa
Consultare esperto in coagulazione
Apixaban Interrompere il farmaco
FFP
fVIIa
Consultare esperto in coagulazione
NOACs: antidotes
aDABI-FAB humanized antibody fragment that
binds dabigatran and reverses its
anticoagulant effects in vitro and
in vivo
PRT064445 catalytically inactive recombinant
protein that lacks the membrane-
binding γ-carboxyglutamic acid
domain of native fXa, while
retaining ability to bind fXa
inhibitors (rivaroxaban, apixaban)
BAY1110262 ??? (rivaroxaban )
Schiele F et al. Blood 2013; Liew A et al. Can J Cardiol 2013
Grazie per l’attenzione