Presentazione standard di PowerPoint - FCSA · Luigi Ria U.O.C. di Medicina Interna Centro Trombosi...

Luigi Ria U.O.C. di Medicina Interna Centro Trombosi ed Emostasi

P.O. “S.Cuore di Gesù” Gallipoli ASL LECCE

"WORKSHOP FCSA"

Milano, 29 maggio 2015

GLI ANTICOAGULANTI DIRETTI (DOAC):

I DOAC NEL TROMBOEMBOLISMO VENOSO E NUOVE POSSIBILI INDICAZIONI

(Cardioversione, FA valvolari, Neoplasie, Pediatria)

Treatment for VTE

Initial (0 to 7 days)

Long-term (7 days to 3-6 months)

Extended (3-6 months to indefinite)

LMWH/FDX VKA VKA or NO TX

Dabigatran/Edoxaban

Rivaroxaban/ Apixaban

Two possible ways

van Es N. et al. Blood 2014; 124 (12): 1968-1975

VTE Recurrence or VTE-related death DOACs vs VKAs

HR 0.90 (95%CI 0.77,1.06)

DOACs compared with VKA for acute venous thromboembolism: evidence from phase 3 trials


Major Bleeding DOACs vs VKAs

HR 0.61 (0.45,0.83)



Other End Point DOACs vs VKAs


Mantha S et al. J Thromb Thrombolysis 2015; 39: 155-165

Indirect comparison of Dabigatran, Rivaroxaban, Apixaban and Edoxaban for the treatment of acute VTE

Prandoni P et al. Haematologica 2007; 92: 199-205

The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1.626 patients

Cumulative incidence of recurrent thromboembolism separately in patients with idiopathic (unprovoked) and secondary VTE

Treatment for VTE





2013

2013

2010

Sardar P et al. Drugs 2013; 73(11):1171-82

Recurrent symptomatic VTE and VTE-related deaths

Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Tromboembolism: Systematic Review and

Meta-Analyses of Randomized Controlled Trials

DOACs vs Placebo

Dabigatran vs VKAs

Major bleeding




DOACs vs Placebo

Dabigatran vs VKAs




Major or Clinically Relevant Nonmajor Bleeding

DOACs vs Placebo

Dabigatran vs VKAs




All-cause mortality

DOACs vs Placebo

Dabigatran vs VKAs

Overview of NOAC trials in VTE

RIVAROXABAN (EINSTEIN DVT and PE)

DABIGATRAN (RE-COVER and RE-COVER II)

EDOXABAN (HOKUSAI VTE)

DABIGATRAN (RE-SONATE + RE-MEDY)

RIVAROXABAN (EINSTEIN – EXTENSION)





APIXABAN 2.5 or 5 mg bid (AMPLFY - EXTENSION)

APIXABAN (AMPLIFY)

LMWH/ FDX

LMWH/ FDX

Cardioversione

Fibrillazione Atriale Valvolare

Profilassi del TEV in Medicina Interna

Neoplasie

Pediatria

NOACs: nuove possibili indicazioni

ESC 2012 update: cardioversion recommendations

Camm AJ et al. Europace 2012; 14: 1385–1413

Recommendation Class Level

For patients with AF of ≥48 hours’ duration, or when the duration of AF is unknown, OAC therapy (e.g. VKA with INR 2–3 or dabigatran) is recommended for ≥3 weeks prior to and for ≥4 weeks after cardioversion, regardless of the method (electrical or oral/i.v. pharmacological)

I B

In patients with risk factors for stroke or AF recurrence, OAC therapy, whether with dose-adjusted VKA (INR 2–3) or a NOAC, should be continued lifelong irrespective of the apparent maintenance of sinus rhythm following cardioversion

I B

RE-LY sottoanalisi cardioversione: Ictus o Embolia Sistemica (entro 30 giorni dalla CV)

Nagarakanti R et al. Circulation 2011;123:131–136

Eventi/numero: 5/647 2/672 4/664

Dabigatran 110 mg BID


Ictu

s/em

bolia

sis

tem

ica

(%)

Warfarin 0

0.3

0.6

0.9

1.2

1.5

1.8

BID = due volte al giorno; CI = intervallo di confidenza; RR = rischio relativo

0.77

0.30

0.60

RR 0.49 (95% CI: 0.09–2.69)

RR 1.28 (95% CI: 0.35–4.76)

P=0.71

P=0.40

RE-LY sottoanalisi cardioversione: Ictus o Embolia Sistemica con o senza TEE

Percentuali analoghe di ictus o embolia sistemica con/senza TEE prima della cardioversione



Warfarin Dabigatran 110 mg BID


Warfarin

P=0.65

P=0.54

P=0.75

P=0.17

TEE prima della cardioversione Senza TEE prima della cardioversione

0.61 0.83

0.39

1.14

0.52

0.0

0.5

1.0

1.5

2.0

2.5

Ictu

s/em

bolia

sis

tem

ica

(%)

0.0


BID = due volte al giorno; TEE = ecocardiogramma transesofageo

Sanguinamenti maggiori <30 giorni dopo cardioversione sono stati poco frequenti in tutti i gruppi


1.5


Warfarin

1.70

0.60 0.60

0.0

0.5

1.0

2.0

2.5

San

guin

amen

ti m

aggi

ori (

%)

11/647

RR 2.82 (95% CI: 0.90–8.82)

RR 0.99 (95% CI: 0.25–3.93)

P=0.06

P=0.99

Eventi/numero: 4/672 4/664

RE-LY sottoanalisi cardioversione: sanguinamenti maggiori


BID = due volte al giorno; TEE = ecocardiogramma transesofageo

Piccinni JP et al. JACC 2013; 61 (19): 1998-2006

Flaker G. et al. JACC 2014; 62 (11): 1082-1087

Design: randomized, open-label, parallel-group, active-controlled multicentre study

Modificata da Ezekowitz MD, et al. Am Heart J 2014;167(5):646-52; www.clinicaltrials.gov.NCT01674647

*15 mg if CrCl 30–49 ml/min; VKA with INR 2.0–3.0; #protocol recommended only if adequate anticoagulation or immediate TEE

30-day follow-up

OAC

Early#

Delayed

Cardioversion strategy

1-5 days R

Rivaroxaban 20 mg od*

VKA

2:1

2:1

≥21 days (max 56 days)


VKA

R

Inclusion criteria: Age ≥18 years, non-valvular AF lasting >48 h or unknown duration, scheduled

for cardioversion

42 days

42 days


VKA


VKA

End

of s

tudy

trea

tmen

t

Car

diov

ersi

on

Car

diov

ersi

on

primary efficacy and safety endpoints

Cappato R, et al. Eur Heart J 2014: doi:10.1093/eurheartj/ehu367.

Cardioversione

Fibrillazione atriale valvolare


Neoplasie

Pediatria


RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE

AF-TIMI 48

RCT NOACs Criteria for defining a valvular AF

Definition of valvular versus non-valvular AF in trials on NOACs based on exclusion criteria

ESC 2010

ESC 2012 Focused update

ACC/AHA/ ESC 2011 AHA/ACC/ HRS 2014

Guideline on AF

Text with the definition

Definitions of valvular versus non-valvular AF according to international consensus guidelines

Esclusione di FA “valvolare”

RE-LY Rocket-AF Aristotle Engage AF

Dabigatran Rivaroxaban Apixaban Edoxaban

Protesi meccanica E E E E

Stenosi mitralica moderata-severa

E E E E

VP severa da operare

E E

Protesi biologica I

Riparazione valvolare (+anello/plastica)

I I I I

RE-LY Ezekowitz MD et al.

ACC 2014 Abs

Rocket AF Breithardt G et al.

EHJ 2014

Aristotle Avezum A et al. ESC 2013 Abs

Tot. trials 18.113 14.171 18.201 Tot . SVD 3.950 21,8% 2.003 14,1% 4.808 26,4% Insuff. Mitralica 3.101 78,5% 1.756 87,7% 3.526 73,3% Insuff. Aortica 817 20,7% 486 24,3% 887 18,4% Stenosi Aortica 471 11,9% 215 10,7% 384 8,0% Insuff.Tricusp. 1.179 29,8% 2.124 44,2% St.Mitralica lieve

193 4,9% 131 2,7%

Precedenti procedure su valvole

106 5,3% 251 5,2%

SVD: considerata significativa dal medico che arruolava per i riflessi sulla pratica clinica

Clinical characteristics and outcomes in AF and native mitral and aortic valve disease in the

ROCKET AF trial

Efficacy: Stroke or systemic embolism

Breithardt G et al. EHJ 2014: 35: 3377-3385

Valvulopatie non emodinamicamente significative, che non necessitano di intervento cardiochirurgico Valvulopatie anche severe, ma differenti dalla stenosi mitralica (2 trial su 3) Interventi di riparazione valvolare senza sotituzione, a differenza di quanto schematizzato nelle linee-guida americane (AHA/ACC 2014)

Secondo i criteri di inclusione nei megatrial, i risultati di efficacia dei NOACs sono stati osservati anche in un

gran numero di pazienti con:

Protesi valvolare meccanica Stenosi mitralica severa Valvulopatia con intervento CCH pianificato

Protesi valvolare biologica Pregressa plastica valvolare + anello TAVI o mitral clip

Valvulopatia moderata + severa (esclusa SM) senza intervento pianificato

NOACs e VALVULOPATIE

?

Ok!

X

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Flarucola.org%2F%3Fattachment_id%3D20099&ei=R0xiVaqrEciR7AaWmIBg&bvm=bv.93990622,d.bGQ&psig=AFQjCNHc4hz7Nyyr3jsNS0gv52kNWlaniA&ust=1432591826715116

Cardioversione



Neoplasie

Pediatria


Apixaban 2.5 mg BID for 30 d. vs

Enoxaparin 40 mg OD for 14 d.

NEJM 2011; 365: 2167-77

Rivaroxaban 10 mg OD for 35 ±4 d. vs

Enoxaparin 40mg OD for 10±4 d.

NEJM 2013; 368: 512-523

0.713 1.334 0.968

Relative risk ratio p=0.0025 for non-inferiority (one-sided)

1.00 0 1.50

Day 10

1.00

0.618 0.962 0.771

Relative risk ratio p=0.0211 for superiority (two-sided)

ARR 1.3%, RRR 22.9%

NEJM 2013; 368: 512-523

Day 35

Rivaroxaban 10 mg OD for 35 ±4 d. vs

Enoxaparin 40mg OD for 10±4 d.

0

NOACs: profilassi del TEV in Medicina Interna

Studio di fase 3

MARINER (Efficacy and safety of Rivaroxaban vs placebo in the prevention of symptomatic VTE and VTE-related death post-hospital discharage in high risk, medically ill patients)

https://clinicaltrials.gov/ct2/show/NCT02111564

Cardioversione



Neoplasie

Pediatria


MAGELLAN and ADOPT: Cancer Patients

Gerotziafas GT et al. Ther Clin Risk Manag 2014;10:423-36

MAGELLAN and ADOPT: Cancer Patients

Gerotziafas GT et al. Ther Clin Risk Manag 2014;10:423-36

Pazienti con Cancro Trials con i DOACs in VTE

Wharin C. Blood Rev 2014; 28 (1):1-8

1058/30989 (3.3%)

NOACs in Acute VTE: Cancer Patients

Vedovati MC et al. CHEST 2015;147(2):475-483

VTE recurrence NOACs vs VKAs

NOACs in Acute VTE: Cancer Patients Major Bleeding

NOACs vs VKA

Vedovati MC et al. CHEST 2015;147(2):475-483

Cardioversione



Neoplasie

Pediatria


Dietrich K. et al. Thromb Res 2015; 135: 630-635

Rivaroxaban ed età pediatrica

14373 – FASE IIa

somministrazione compresse o sciroppo (20 mg/die) per 30 giorni dopo almeno 2 mesi di trattamento standard

Popolazione con VTE di età compresa tra i 6 anni < 18 anni (completata la coorte 12-18, ora aperta la coorte 6 anni < 12 anni)

Fine arruolamento: Novembre 2015

Rivaroxaban ed età pediatrica

14373 – fase IIa: obiettivi

The primary objective of the study is:

to investigate the occurrence of major bleeding and clinically relevant non-major bleeding

The secondary objectives of the study are:

to characterize the safety and PK/PD profile of a 30-day treatment of rivaroxaban tablets or oral suspension

to investigate the occurrence of recurrent venous thromboembolism

s.c.LMWH or VKA End

of s

tudy

tr

eatm

ent

Rivaroxaban 20 mg once daily

Follo

w-u

p vi

sit Pediatric subjects

aged ≥6 years to <18 years with

documented prior venous

thromboembolism

Day 30 +/-3 days

Day 60+/-7 days

R

N=20

Overall Study Design

Prior standard of care treatment for at least

60 days

Observational Period

Approx.30 days

Screening Day-60 to -15

Baseline Day 0

N=20

Interim Visit Day 15 +/-3 days

V1

Screening Day-60 to -15

V2

Randomization

Day 0

V3

Interim

Day 15 +/-3 days

V4

End of treatment

30 +/- 3 days

V5

Follow-up

60 +/- 7 days

NOACs: Take home messages

I NOACs hanno efficacia analoga ai VKAs nel trattamento del TEV acuto, ma sono più sicuri

Nel trattamento esteso del TEV sono associati ad un basso rischio emorragico

Limitate evidenze nei pazienti con cancro

Pari sicurezza vs warfarin nei pazienti sottoposti a cardioversione

Possibile impiego in alcune valvulopatie escluse le protesi valvolari meccaniche, la stenosi mitralica e le valvulopatie severe con intervento CCH pianificato

Non indicazione nella profilassi primaria del paziente con patologia internistica acuta

Al momento non ci sono evidenze per l’impiego in pediatria

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