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

http://www.google.it/url?url=http://www.bmj.com/company/products-services/&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwi00ZOQo8jMAhWBSBQKHa9qD4IQwW4IJjAI&usg=AFQjCNFpq8JbCUhbM41W2a4OTteWlCUcJA

http://www.google.it/url?url=http://www.bmj.com/company/products-services/&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwi00ZOQo8jMAhWBSBQKHa9qD4IQwW4IJjAI&usg=AFQjCNFpq8JbCUhbM41W2a4OTteWlCUcJA

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

http://th.schattauer.de/en/contents/current-issue.html

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

https://www.dailybest.it/2013/10/22/i-10-colleghi-da-evitare-per-la-pausa-pranzo/pausa_pranzo/

Grazie per l’attenzione